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Cited by 62Antifungal resistance and susceptibilitySepsis Diagnosis and TreatmentFungal Infections and Studies

Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting

Open access
Lepak, Alexander, Andes, David·2011·Critical Care Clinics
DOI 10.1016/j.ccc.2010.11.001
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Abstract

Invasive fungal infections (IFI) and fungal sepsis in the intensive care unit are increasing and are associated with considerable morbidity and mortality. In this setting, IFI are predominantly caused by Candida species. Outcomes continue to be suboptimal; however, there are a few key clinician modifiable factors. PK-PD studies with the approved antifungal agents have provided guidance on the dosing strategy that predicts improved outcome. In addition, time to therapy is a critical element. Therefore early recognition through improved risk factor analysis and diagnostics will be key developments. Source control for infected devices and endophthalmitis must be considered.

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Crossref · 10.1016/j.ccc.2010.11.001

Cites

194 of 194 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 156 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In the intensive care unit, invasive fungal infections are predominantly caused by Candida species.

    “In this setting, IFI are predominantly caused by Candida species.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Wisplinghoff, 2004, Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study, Clin Infect Dis source

      Not checked in the free run.

    • cites [2] Hidron, 2008, NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007, Infect Control Hosp Epidemiol source

      Not checked in the free run.

    • cites [3] Pfaller, 2007, Epidemiology of invasive candidiasis: a persistent public health problem, Clin Microbiol Rev source

      Not checked in the free run.

  • Premisecitation

    In multivariate analysis, the odds of death were twofold higher if adequate therapy was delayed more than 12 hours (P = .018).

    “In multivariate analysis the odds of death was 2-fold higher if adequate therapy was delayed more than 12 hours (P 5 .018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Morrell, 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 source

      Not checked in the free run.

  • Premisecitation

    In a cohort of patients with cancer, Taur and colleagues found similar results supporting early appropriate antifungal therapy.

    “Another recent publication by Taur and colleagues 49 in a cohort of patients with cancer found similar results.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Taur, 2010, Effect of antifungal therapy timing on mortality in cancer patients with candidemia, Antimicrob Agents Chemother source

      Not checked in the free run.

  • Premisecitation

    Multivariate analysis in the Garey study showed a strong association between delay in therapy and mortality.

    “Multivariate analysis in this study also provided a strong association between delay in therapy and mortality.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Garey, 2006, Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study, Clin Infect Dis source

      Not checked in the free run.

  • Interpretationreasoning

    Knowledge of local epidemiology is imperative for selecting appropriate empirical therapy for invasive candidiasis.

    “As C glabrata often exhibits reduced susceptibility to triazoles and C parapsilosis has reduced susceptibility to echinocandins, knowledge of the local epidemiology is imperative for selection of appropriate empirical therapy.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 39
  • May combine two claims. 43
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Invasive fungal infections and fungal sepsis in the intensive care unit are increasing and are associated with considerable morbidity and mortality.

    “Invasive fungal infections (IFI) and fungal sepsis in the intensive care unit (ICU) are increasing and are associated with considerable morbidity and mortality.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Wisplinghoff, 2004, Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study, Clin Infect Dis source

      Not checked in the free run.

    • cites [2] Hidron, 2008, NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007, Infect Control Hosp Epidemiol source

      Not checked in the free run.

    • cites [3] Pfaller, 2007, Epidemiology of invasive candidiasis: a persistent public health problem, Clin Microbiol Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Candidemia is currently the fourth most common health care-associated bloodstream infection.

    “Currently, candidemia represents the fourth most common health care-associated blood stream infection.[1][2][3]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Wisplinghoff, 2004, Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study, Clin Infect Dis source

      Not checked in the free run.

    • cites [2] Hidron, 2008, NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007, Infect Control Hosp Epidemiol source

      Not checked in the free run.

    • cites [3] Pfaller, 2007, Epidemiology of invasive candidiasis: a persistent public health problem, Clin Microbiol Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    With increasingly immunocompromised patient populations, other fungal species such as Aspergillus, Pneumocystis jiroveci, Cryptococcus, Zygomycetes, Fusarium, and Scedosporium have emerged.

    “With increasingly immunocompromised patient populations, other fungal species such as Aspergillus species, Pneumocystis jiroveci, Cryptococcus, Zygomycetes, Fusarium species, and Scedosporium species have emerged.[4][5][6][7][8][9]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Maschmeyer, 2007, Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients, Drugs source

      Not checked in the free run.

    • cites [5] Meersseman, 2007, Invasive aspergillosis in the intensive care unit, Clin Infect Dis source

      Not checked in the free run.

    • cites [6] Meersseman, 2004, Invasive aspergillosis in critically ill patients without malignancy, Am J Respir Crit Care Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These data strongly support early appropriate antifungal therapy and demonstrate a need for improved disease identification.

    “These data strongly support early appropriate antifungal therapy and demonstrate a need for improved disease identification.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a retrospective cohort, adequate antimicrobial therapy within the first hour of documented hypotension was associated with a survival rate of 79.9%, and each 1-hour delay was linked to a 7.6% per hour decrease in survival.

    “Another retrospective cohort study by Kumar and colleagues 34 demonstrated that administration of adequate antimicrobial therapy within the first hour of documented hypotension was associated with a survival rate of 79.9%, and each 1-hour delay in antimicrobial therapy was linked to a 7.6% per hour decrease in survival.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Kumar, 2006, Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock, Crit Care Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The added hospital cost from candidemia is as much as $40,000 per case.

    “Estimates from numerous studies suggest the added hospital cost is as much as $40,000 per case.[10][11][12][16][17][18][19][20]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Morgan, 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 source

      Not checked in the free run.

    • cites [11] Pelz, 2000, Candida infections: outcome and attributable ICU costs in critically ill patients, J Intensive Care Med source

      Not checked in the free run.

    • cites [12] Zaoutis, 2005, The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis, Clin Infect Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Candida bloodstream infection increased by more than 200% from 1979 to 2000.

    “This trend continued with a greater than 200% increase from 1979 to 2000.23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Martin, 2003, The epidemiology of sepsis in the United States from 1979 through 2000, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overall attributable costs of candidemia in the United States have been estimated to be close to 1 billion dollars annually.

    “Overall attributable costs are difficult to calculate with precision, but have been estimated to be close to 1 billion dollars in the United States annually.21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Miller, 2001, Estimating the cost of nosocomial candidemia in the United States, Clin Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Candida glabrata often has reduced susceptibility to triazoles, and Candida parapsilosis has reduced susceptibility to echinocandins.

    “As C glabrata often exhibits reduced susceptibility to triazoles and C parapsilosis has reduced susceptibility to echinocandins, knowledge of the local epidemiology is imperative for selection of appropriate empirical therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Inappropriate treatment was most common for Enterococcus species, but inadequate coverage for invasive candidiasis was the second most common error and was associated with the highest mortality.

    “Inappropriate treatment was most common for Enterococcus spp; however, inadequate coverage for IC was the second most common error and was associated with the highest mortality.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Ibrahim, 2000, The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting, Chest source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    These care themes are similar to those for bacterial sepsis, but many features are unique to invasive candidiasis.

    “These care themes are similar to those of demonstrated importance for bacterial sepsis, yet many features are unique to IC.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Current rates of Candida bloodstream infection are estimated at 25 to 30 per 100,000 persons.

    “The shift in the epidemiology of this health care-associated infection has continued in the current decade, with rates now estimated to be between 25 and 30 per 100,000 persons.16,24”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Shorr, 2009, Burden of early-onset candidemia: analysis of culture-positive bloodstream infections from a large U.S. database, Crit Care Med source

      Not checked in the free run.

    • cites [24] Zilberberg, 2008, Secular trends in candidemia-related hospitalization in the United States, 2000–2005, Infect Control Hosp Epidemiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mortality attributable to candidemia, estimated by carefully matched retrospective cohort studies, ranges from 10% to 49%.

    “Carefully matched, retrospective cohort studies have been undertaken to estimate mortality attributable to candidemia and report rates ranging from 10% to 49%.[10][11][12][13][14][15]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Morgan, 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 source

      Not checked in the free run.

    • cites [11] Pelz, 2000, Candida infections: outcome and attributable ICU costs in critically ill patients, J Intensive Care Med source

      Not checked in the free run.

    • cites [12] Zaoutis, 2005, The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis, Clin Infect Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Candida albicans has historically been the predominant pathogen in invasive candidiasis, with rates of 80% or higher in the 1980s.

    “C albicans has historically been the predominant pathogen in IC with rates of 80% or higher in the 1980s.3,25”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Pfaller, 2007, Epidemiology of invasive candidiasis: a persistent public health problem, Clin Microbiol Rev source

      Not checked in the free run.

    • cites [25] Snydman, 2003, Shifting patterns in the epidemiology of nosocomial Candida infections, Chest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with invasive candidiasis, mortality was 78% when therapy was delayed more than 48 hours from onset of candidemia, compared with 44% in those who received adequate initial therapy.

    “Blot and colleagues 42 reported 78% mortality in patients with IC when therapy was delayed more than 48 hours from onset of candidemia; in contrast the mortality was 44% in those who had adequate initial therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Blot, 2002, Effects of nosocomial candidemia on outcomes of critically ill patients, Am J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with invasive candidiasis have excessive rates of inappropriate initial therapy and higher mortality than intensive care unit patients with bacterial infections.

    “Studies on patients with IC have similarly shown excessive rates of inappropriate initial therapy and even higher mortality than infections caused by bacterial pathogens in the ICU setting.10,14,33,34,[42][43][44][45][46][47]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Morgan, 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 source

      Not checked in the free run.

    • cites [14] Gudlaugsson, 2003, Attributable mortality of nosocomial candidemia, revisited, Clin Infect Dis source

      Not checked in the free run.

    • cites [33] Ibrahim, 2000, The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting, Chest source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Crude mortality in patients with candidemia ranges from 46% to 75% in retrospective studies.

    “Multiple retrospective studies have examined the crude mortality in patients with candidemia and identified rates ranging from 46% to 75%. 3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Pfaller, 2007, Epidemiology of invasive candidiasis: a persistent public health problem, Clin Microbiol Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Care strategies of demonstrated relevance for invasive candidiasis include prompt suspicion, rapid evaluation, diagnosis, initiation of antimicrobial therapy, choice of optimal agent and dosing, and source control.

    “The care strategies of demonstrated relevance include prompt suspicion of IC, rapid evaluation, diagnosis and initiation of antimicrobial therapy.In addition, the optimal agent to target these pathogens and the proper dosing regimen must be chosen, and source control should be considered.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    For time-dependent antimicrobials, the optimal regimen aims to keep drug concentrations above the MIC for a longer period, and the predictive index is %T>MIC.

    “The optimal regimen design in this case would aim to keep drug concentrations higher than the organism's MIC for a longer period of time and the predictive index for these antimicrobials is the %T>MIC.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisereasoning

    For concentration-dependent antimicrobials, dosing is optimal when large doses are given infrequently.

    “For example, dosing of concentration-dependent antimicrobials is optimal when large doses are administered infrequently.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    At present, there is significant heterogeneity in assay characteristics including choice of sample, primer, nesting strategy, and nucleic acid extraction.

    “At present, there is significant heterogeneity in assay characteristics including choice of sample, primer, nesting strategy, and nucleic acid extraction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The gold standard diagnostic test for invasive candidiasis has been isolation of the organism in blood culture, but blood culture for Candida is insensitive.

    “In addition, the gold standard diagnostic test for IC has been isolation of the organism in blood culture, however, blood culture for Candida is insensitive.[52][53][54][55]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [52] Darouiche, 2009, Candida in the ICU, Clin Chest Med source

      Not checked in the free run.

    • cites [53] Zilberberg, 2009, Fungal infections in the ICU, Infect Dis Clin North Am source

      Not checked in the free run.

    • cites [54] Berenguer, 1993, Lysis-centrifugation blood cultures in the detection of tissue-proven invasive candidiasis. Disseminated versus single-organ infection, Diagn Microbiol Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sensitivities were 40% and 98%, and specificities were 53% and 94%, for mannanemia and antibody detection, respectively.

    “The sensitivities were 40% and 98% and the specificities were 53% and 94% for mannanemia or antibody detection, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Sendid, 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study by Fernandez and colleagues, mean time to yeast detection in blood cultures was 35.3 ± 18.1 hours for Candida albicans and 80.0 ± 22.4 hours for Candida glabrata.

    “In a study by Fernandez and colleagues, 56 the mean time to yeast detection in blood cultures for C albicans was 35.3 Æ 18.1 hours, whereas that of C glabrata was 80.0 Æ 22.4 hours.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Fernandez, 2009, Time to positive culture and identification for Candida blood stream infections, Diagn Microbiol Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The importance of prompt antifungal treatment and the lack of sensitivity and timeliness of diagnostic assays has led to the development of empirical and preemptive treatment strategies.

    “The importance of prompt antifungal treatment and lack of sensitivity and timeliness of diagnostic assays has led to the development of empirical and preemptive treatment strategies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    SeptiFast, which detects DNA of 20 common bacteria and fungi, may be a helpful adjunct to blood cultures for fastidious organisms and may be advantageous in settings where patients are already on antibiotics or have been pretreated.

    “SeptiFast, which is able to detect DNA of 20 common bacteria and fungi, may be a helpful adjunct to blood cultures for fastidious organisms and may be advantageous in settings where patients are either already on antibiotics or have been pretreated.65,66”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Vince, 2008, LightCycler SeptiFast assay as a tool for the rapid diagnosis of sepsis in patients during antimicrobial therapy, J Med Microbiol source

      Not checked in the free run.

    • cites [66] Yanagihara, 2010, Evaluation of pathogen detection from clinical samples by real-time polymerase chain reaction using a sepsis pathogen DNA detection kit, Crit Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    If empirical trial use of the beta-1,3-D-glucan test is shown to be useful, it is reasonable to expect this assay could be adapted for use in most tertiary care centers in the near future.

    “If the empirical trial use of the b-1, 3-D-glucan test is shown to be useful, it is reasonable to expect this assay could be adapted for use in most tertiary care centers in the near future.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The concentration-dependent indices Cmax/MIC and AUC/MIC are associated with treatment efficacy for concentration-dependent antimicrobials.

    “The concentrationdependent indices, C max /MIC and AUC/MIC, are the PD indices associated with treatment efficacy for these compounds.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Until confirmatory results from ongoing studies are available, routine use of these new diagnostic assays will remain investigative.

    “Until confirmatory results are available from ongoing studies, routine use of these new diagnostic assays will remain investigative.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisereasoning

    For time-dependent antimicrobials, maximal antimicrobial effects are observed at concentrations near the MIC.

    “In this scenario, maximal antimicrobial effects are observed at concentrations near the MIC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Although promising, these diagnostic tools need further prospective validation and wider availability, as currently only a few academic centers or reference laboratories can offer these advanced diagnostic techniques.

    “Although promising, there is need for further prospective validation of these diagnostic tools and wider availability, as currently only a few academic centers or reference laboratories have the capability to offer these advanced diagnostic techniques.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    For time-dependent antimicrobials, efficacy is greatest when smaller doses are given frequently.

    “Conversely, efficacy for antimicrobials that exhibit time-dependent activity is greatest when smaller doses are given frequently.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Detection of candidemia by blood culture often takes more than 24 hours, and for species such as Candida glabrata the time to positive culture can be even longer.

    “Furthermore, detection of candidemia by blood culture often takes more than 24 hours.For certain species, such as C glabrata, the time to positive culture can be even longer.[56][57][58][59][60]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [56] Fernandez, 2009, Time to positive culture and identification for Candida blood stream infections, Diagn Microbiol Infect Dis source

      Not checked in the free run.

    • cites [57] Ben-Ami, 2008, Time to blood culture positivity as a marker for catheter-related candidemia, J Clin Microbiol source

      Not checked in the free run.

    • cites [58] George, 2005, Effect of inoculum size on detection of Candida growth by the BACTEC 9240 automated blood culture system using aerobic and anaerobic media, J Clin Microbiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The estimated clinical sensitivity, specificity, positive predictive value, and negative predictive value of the PCR assays were 90.9%, 100%, 100%, and 99.8%, respectively.

    “The estimated clinical sensitivity, specificity, and positive and negative predictive values of the assays in this trial were 90.9%, 100%, 100%, and 99.8%, respectively.64”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] McMullan, 2008, A prospective clinical trial of a real-time polymerase chain reaction assay for the diagnosis of candidemia in nonneutropenic, critically ill adults, Clin Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Waiting for positive blood culture results and potentially susceptibility testing leads to significant delay in appropriate therapy and in turn higher mortality.

    “Thus, waiting for positive blood culture results and potentially susceptibility testing leads to a significant delay in appropriate therapy and in turn higher mortality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Variables associated with invasive candidiasis include high APACHE II score, exposure to broad-spectrum antibiotics, cancer chemotherapy, mucosal colonization by Candida spp, pancreatitis, indwelling vascular catheters (especially central venous catheter), total parenteral nutrition, neutropenia, immune suppression therapy, prior surgery (especially gastrointestinal surgery), renal failure or haem

    “Variables that have been associated with IC include high APACHE II score, exposure to broad spectrum antibiotics, cancer chemotherapy, evidence of mucosal colonization by Candida spp, pancreatitis, indwelling vascular catheters (especially central venous catheter [CVC]), administration of total parenteral nutrition, neutropenia, immune suppression therapy, prior surgery (especially gastro”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [51] Ostrosky-Zeichner, 2006, Invasive candidiasis in the intensive care unit, Crit Care Med source

      Not checked in the free run.

    • cites [68] Wey, 1989, Risk factors for hospital-acquired candidemia. A matched case-control study, Arch Intern Med source

      Not checked in the free run.

    • cites [69] Blumberg, 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 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Determining which of the three pharmacodynamic indices predicts efficacy for an antimicrobial provides a framework for designing dosing regimens.

    “Determining which of the 3 PD indices is predictive of efficacy for an antimicrobial agent provides a framework for dosing regimen design.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The IDSA guideline for invasive candidiasis recommends a 2-week treatment duration following clearance of Candida from the bloodstream and resolution of symptoms attributable to candidemia.

    “The IDSA guideline for invasive candidiasis recommends a 2-week treatment duration following clearance of Candida from the bloodstream and resolution of symptoms attributable to candidemia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Pappas, 2009, Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America, Clin Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The concentration-dependent indices Cmax/MIC and AUC/MIC are both closely linked to efficacy for echinocandins and support administration of large infrequent doses.

    “The concentration-dependent indices, C max /MIC and AUC/MIC, are both closely linked to efficacy and support administration of large infrequent doses.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [156] Andes, 2003, In vivo pharmacodynamics of HMR 3270, a glucan synthase inhibitor, in a murine candidiasis model, Antimicrob Agents Chemother source

      Not checked in the free run.

    • cites [157] Andes, 2008, In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model, Antimicrob Agents Chemother source

      Not checked in the free run.

    • cites [158] Andes, 2008, In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model, Antimicrob Agents Chemother source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C. albicans has the lowest wild-type MICs, with 98.1% having an MIC of 0.5 mg/mL or less.

    “C albicans has the lowest wild-type MICs with 98.1% having an MIC of 0.5 mg/mL or less.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Pfaller MA, Andes D, Diekema DJ, et al. Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: time for harmonization of CLSI and EUCAST broth microdilution methods. Paper presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy. Boston (MA), September 12–15, 2010.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Results from this investigation found a free drug AUC/MIC target of greater than 7.5 was associated with favorable outcomes for all Candida species except C. parapsilosis, for which a free drug AUC/MIC magnitude predictive of favorable outcome was near 1.

    “Results from this investigation found a free drug AUC/MIC target of greater than 7.5 was associated with favorable outcomes for all Candida species except C parapsilosis, for which a free drug AUC/ MIC magnitude predictive of favorable outcome was near 1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Andes DR, Ambrose PG, Hammel JP, et al. Exposure-response (E-R) relationships for efficacy of micafungin in patients with invasive candidiasis (IC). Paper presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, September 12–15, 2009.

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Longer durations are recommended for persistent candidemia and for metastatic infection involving other sites (CNS, bone, endocarditis, joint/prosthetic joint infection).

    “Longer durations are recommended for persistent candidemia and for metastatic infection involving other sites (ie, CNS, bone, endocarditis, joint/ prosthetic joint infection).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Pappas, 2009, Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America, Clin Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Thus, dose adjustments should not be needed at present for echinocandins, but if surveillance susceptibility testing identifies the emergence of less susceptible isolates, safety studies with each of the available echinocandin compounds can be escalated without toxicity.

    “Thus, although Fungal Sepsis dose adjustments should not be needed at present, if surveillance susceptibility testing identifies the emergence of less susceptible isolates, safety studies with each of the available echinocandin compounds can be escalated without toxicity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    Guidance for duration of therapy for invasive candidiasis is based on expert consensus publications.

    “Guidance is based on expert consensus publications.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The PK/PD congruency in target AUC/MIC between Aspergillus and Candida suggests target trough concentrations should be at least 1 to 2 mg/mL for invasive candidiasis and concentration monitoring might be useful in the critical care setting.

    “Although not well studied in IC, the PK/PD congruency in target AUC/MIC between Aspergillus and Candida would suggest target trough concentrations should be at least 1 to 2 mg/mL for IC and concentration monitoring might be useful in the critical care setting.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Andes, 2009, Antifungal therapeutic drug monitoring: established and emerging indications, Antimicrob Agents Chemother source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Therapeutic success was observed in approximately 80% of patients with a voriconazole 24-hour AUC/MIC greater than 25, whereas clinical failure was noted in 45% of patients with AUC/MIC less than 25.

    “Therapeutic success was observed in approximately 80% of patients with a 24-hour AUC/MIC greater than 25, whereas when the AUC/MIC was less than 25, clinical failure was noted in 45% of patients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] Pfaller, 2006, Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints, J Clin Microbiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Studies with fluoroquinolone antibacterials identified an AUC/MIC target for Streptococcus pneumoniae of 25, whereas for gram-negative bacteria the value was near 100.

    “For example, studies with fluoroquinolone antibacterials identified an AUC/MIC target for Streptococcus pneumoniae of 25, whereas for gram-negative bacteria the value was near 100.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Ambrose, 2007, Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore, Clin Infect Dis source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Treatment guidelines recommend step down to fluconazole for patients who have improved clinically after initial therapy with an echinocandin or amphotericin B and who are infected with an organism likely susceptible to fluconazole (e.g., C. albicans, C. parapsilosis, C. tropicalis) or if there is documented susceptibility based on laboratory MIC testing.

    “Treatment guidelines recommend step down to fluconazole for patients who have improved clinically after initial therapy with an echinocandin or amphotericin B and who are infected with an organism that is likely to be susceptible to fluconazole (eg, C albicans, C parapsilosis, and C tropicalis) or if there is documented susceptibility based on laboratory MIC testing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Pappas, 2009, Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America, Clin Infect Dis source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    The timing of step down has not been specifically analyzed in these investigations.

    “However, the timing of step down has not been specifically analyzed in these investigations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    With a fluconazole dose of 400 mg once daily and an MIC of 32, the AUC/MIC would be less than 25 and failure can be expected.

    “For example, with a fluconazole dose of 400 mg once daily for an infection in which the MIC is 32, the AUC/MIC would be less than 25 and failure can be expected.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a single randomized clinical trial comparing high-dose fluconazole versus standard fluconazole dosing and amphotericin B in patients with candidemia, there was a trend in favor of the combination for several outcomes, but the 2 groups had significant differences in baseline APACHE II score favoring the combination arm.

    “For several outcomes there was a trend in favor of the combination; however, the 2 groups had significant differences in baseline APACHE II score favoring the combination arm.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Rex, 2003, A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects, Clin Infect Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Deescalation or step down therapy from intravenous echinocandin or polyene to oral therapy is a common strategy but has not been formally studied.

    “Deescalation or step down therapy from intravenous echinocandin or polyene to oral therapy is a common strategy but has not been formally studied.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The free drug AUC/MIC target for echinocandins was approximately 5 to 7 for C. parapsilosis and C. glabrata, whereas for C. albicans the target AUC/MIC was approximately 10 to 20.

    “The free drug AUC/MIC target was much less for C parapsilosis and C glabrata at approximately 5 to 7, whereas for C albicans the target AUC/MIC was approximately 10 to 20.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [165] Andes, 2010, In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species, Antimicrob Agents Chemother source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    For other species, the therapy should be directed based on susceptibility data.

    “For other species, the therapy should be directed based on susceptibility data.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Therefore, the current guidelines suggest ophthalmologic examination for every patient with candidemia.

    “Therefore, the current guidelines suggest ophthalmologic examination for every patient with candidemia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Pappas, 2009, Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America, Clin Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although not studied in randomized comparative trials, vitrectomy is considered an important adjunct to antifungal therapy and can be a sight-saving procedure.

    “Although not studied in randomized comparative trials, vitrectomy is considered an important adjunct to antifungal therapy and can be a sight-saving procedure.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Essman, 1997, Treatment outcomes in a 10-year study of endogenous fungal endophthalmitis, Ophthalmic Surg Lasers source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims. The quote only partly states this claim.

    Interpretationnone given

    Critical components in the management of antifungal sepsis that are clinician mitigated include prompt antifungal therapy, risk factor analysis to identify patients at higher risk than the general ICU population for IC and therefore in need of prophylactic or preemptive therapy given the current lack of prompt accurate diagnostics, choice of the appropriate antifungal agent and dosing regimen, and

    “Critical components in the management of antifungal sepsis that are clinician mitigated include (1) prompt antifungal therapy, (2) risk factor analysis to identify patients at higher risk than the general ICU population for IC and therefore in need of prophylactic or preemptive therapy given the current lack of prompt accurate diagnostics, (3) choice of the appropriate antifungal agent and dosing”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A few studies have questioned these recommendations, failing to find a significant mortality benefit with prompt removal of the line and advising that removal and placement of a new device does not come without risk and cost.

    “A few studies have questioned these recommendations, failing to find a significant mortality benefit with prompt removal of the line and advising that removal and placement of a new device does not come without risk and cost.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [179] Nucci, 1998, Risk factors for death among cancer patients with fungemia, Clin Infect Dis source

      Not checked in the free run.

    • cites [180] Rodriguez, 2007, Impact of early central venous catheter removal on outcome in patients with candidaemia, Clin Microbiol Infect source

      Not checked in the free run.

    • cites [181] Velasco, 2008, A prospective cohort study evaluating the prognostic impact of clinical characteristics and comorbid conditions of hospitalized adult and pediatric cancer patients with candidemia, Eur J Clin Microbiol Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    If an at-risk group with an infection rate of at least 10% could be reliably identified, the number needed to treat to prevent 1 infection would be less than 20, and this can be considered a potentially useful strategy for that specific patient group.

    “If an at-risk group with an infection rate of at least 10% could be reliably identified, the number needed to treat to prevent 1 infection would be less than 20, and certainly this can be considered a potentially useful strategy for that specific patient group.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Source control, including line removal and evaluation for endophthalmitis, is recommended for all patients with invasive candidiasis.

    “Source control, including line removal and evaluation for endophthalmitis is recommended for all patients with IC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A few meta-analyses have suggested potential mortality benefits with fluconazole prophylaxis; however, with an incidence of 1% to 2% in most ICU populations, more than 200 patients would need to undergo prophylaxis to prevent 1 infection.

    “A few meta-analyses have suggested potential mortality benefits with fluconazole prophylaxis; however, with an incidence of 1% to 2% in most ICU populations, more than 200 patients would need to undergo prophylaxis to prevent 1 infection.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [185] Rex, 2001, Prophylactic antifungal therapy in the intensive care unit, Clin Infect Dis source

      Not checked in the free run.

    • cites [186] Viscoli, 2009, Antifungal prophylaxis and pre-emptive therapy, Drugs source

      Not checked in the free run.

    • cites [187] Playford, 2010, Prophylaxis, empirical and preemptive treatment of invasive candidiasis, Curr Opin Crit Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Recommended antifungal therapies for endophthalmitis include amphotericin B, fluconazole, or voriconazole depending on the susceptibility of the isolate.

    “Recommended antifungal therapies include amphotericin B, fluconazole, or voriconazole depending on the susceptibility of the isolate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Therefore, it is necessary to consider prophylaxis strategies in high-risk individuals, pointing to the need for better risk stratification schemes in the ICU.

    “Therefore, it is necessary to consider prophylaxis strategies in high-risk individuals, pointing to the need for better risk stratification schemes in the ICU.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The value of preemptive therapy has been best documented in the persistently neutropenic patient, and current guidelines suggest adding a broad spectrum antifungal agent in a neutropenic patient with persistent fever for 5 days despite broad spectrum antibiotics.

    “The value of preemptive therapy has been best documented in the persistently neutropenic patient, and current guidelines suggest adding a broad spectrum antifungal agent in a neutropenic patient with persistent fever for 5 days despite broad spectrum antibiotics.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Hughes, 2002, 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer, Clin Infect Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Currently, until a species diagnosis or susceptibility is known, an echinocandin is recommended as first-line therapy for most patients with invasive candidiasis.

    “Currently, until a species diagnosis or susceptibility is known, an echinocandin is recommended as first-line therapy for most patients with IC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Endophthalmitis is a not uncommon complication in patients with candidemia, with an incidence ranging from 3% to 28% in prospective studies, and carries significant morbidity.

    “Endophthalmitis is a not uncommon complication in patients with candidemia, with an incidence ranging from 3% to 28% in prospective studies, and carries significant morbidity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Gauthier, 2005, Subtherapeutic ocular penetration of caspofungin and associated treatment failure in Candida albicans endophthalmitis, Clin Infect Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    There is interest in monitoring nonculture-based diagnostic tests in critically ill patients (such as b-glucan) to identify patients on the threshold of sepsis.

    “In addition, there is interest in monitoring nonculture-based diagnostic tests in critically ill patients (such as b-glucan) to identify patients on the threshold of sepsis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Improved risk stratification schemes should allow for more directed preemptive therapy in high-risk groups.

    “Improved risk stratification schemes should allow for more directed preemptive therapy in high-risk groups.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    The rationale for source control includes removal of persistent infection and decreasing the infectious burden at pharmacologically protected sites.

    “The rationale for source control includes removal of persistent infection and decreasing the infectious burden at pharmacologically protected sites.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Once the species is identified, for C. albicans, C. parapsilosis, or C. tropicalis and the patient is responding to initial therapy, the appropriate therapy would include step down to fluconazole.

    “Once the species is identified, for C albicans, C parapsilosis, or C tropicalis and the patient is responding to initial therapy, the appropriate therapy would include step down to fluconazole.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The accumulation of therapeutic agents in the vitreous is limited for many compounds and there is variability among the available antifungal agents.

    “The accumulation of therapeutic agents in the vitreous is limited for many compounds and there is variability among the available antifungal agents.”
    Quote in the paperNot a substantial claim
71 of 71

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?

  • High doses of antimicrobials can cause liver and kidney damages.

    “With the development of resistance and the fact that high doses of antimicrobials can cause liver and kidney damages [86], new molecules active against C. albicans, preventing biofilm formation or destroying its integrity, are certainly needed”

    From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [86]

  • Because fungal biofilms are largely resistant to current antifungal drugs, high antifungal doses together with removal of the colonized medical device are generally required to treat infections.

    “Because fungal biofilms are largely resistant to current antifungal drugs, high antifungal doses together with removal of the colonized medical device are generally required to treat infections (6, 29, 104, 112, 121).”

    From <i>Candida albicans</i> Biofilms and Human Disease (2015) · cites this paper as [104]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Combined mannan testing is reported as less sensitive than antibody testing alone

    Major

    The reported 80% sensitivity for the combined tests is lower than the 98% sensitivity reported for antibody detection alone. Testing positive on either assay cannot identify fewer cases than antibody detection alone in the same patients.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Andes DR, Safdar N, Baddley J, et al. Impact of therapy on mortality across Candida spp in patients with invasive candidiasis from randomized clinical trials: a patient level analysis. Paper presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy. Boston (MA), September 12–15, 2010.
  2. Andes DR, Ambrose PG, Hammel JP, et al. Exposure-response (E-R) relationships for efficacy of micafungin in patients with invasive candidiasis (IC). Paper presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, September 12–15, 2009.

Cited by

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Related

Authors
Lepak, A., & Andes, D.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Andes, David
ORCID
Venue
Critical Care Clinics
Publisher
Elsevier BV
Published
2011-01
Volume
27
Issue
1
Pages
123-147
ISSN
0749-0704 (ISSN-L)
DOI
10.1016/j.ccc.2010.11.001
OpenAlex
W2114536396
Semantic Scholar
99e2d352913268a58f1080c545b798ca6b6eca0b
Cited by
62
References
194
Citations by year
2026: 2 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 8 · 2019: 6 · 2017: 1 · 2016: 3 · 2015: 6 · 2014: 4 · 2013: 4 · 2012: 5
FWCI
0.52
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Critical Care Clinics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
fungal sepsis, invasive fungal infections, candidemia, invasive candidiasis, antifungal therapy, intensive care unit, Candida, mortality, health care costs, immunocompromised patients, Aspergillus, Pneumocystis jirovecii, Cryptococcus, Zygomycetes, Fusarium, Scedosporium
MeSH terms
Antifungal Agents, Candida, Critical Care, Humans, Intensive Care Units, Fungemia, Candidemia

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.

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