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SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
SEYED MOHAMMADREZA Hashemian IFI
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SEYED MOHAMMADREZA Hashemian IFI

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IFI in Critical Care setting an unproven story

IFI in Critical Care setting an unproven story

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  • In this presentation we will look at the role for the echinocandins in the management of fungal infections within the ICU.
  • Candidaemia is one of the most common presentations of invasive candidiasis, and also the one that gets the bulk of the attention in the literature. It is important to put candidaemia firmly in context. Candida is the 4 th most common cause of nosocomial bloodstream infection in the US, and the third most common ICU nosocomial bloodstream infection in many studies. It represents around 10% of all nosocomial bloodstream infections and is a very dangerous entity. Crude mortality rates exceed those of staphylococcal bacteraemia at up to 50% in the ICU. The mortality attributable directly to the candida is currently thought to be between 15 and 25, and does seem to have declined in the last 10 years or so. Some studies, particularly those from the US where there is more widespread use of azole prophylaxis, have demonstrated a rise in infections with non-albicans species. This has probably not seen its full expression in our ICUs as yet.
  • Going back to our epidemiology, Candida infections are a clear sign of the status of your patient and their immune state. ICU patients have multiple risk factors for invasive candida infections and there have been many papers providing lists of these. However, these two papers present a very clear evidence-based picture of factors that combine in our patients to increase their risk. As you will see these are common factors and basically all of our ICU patients are at increased risk...the more factors the higher that risk and this has led to prophylactic azole therapy in these patients. I am not going to look at prophylaxis in this talk, except to say that it is effective in terms of infection and outcome in some studies, although not consistently, and has been linked to the development of azole resistance.
  • I have not considered prophylactic therapy here. The trial data is mainly on empirical or targeted therapy.
  • TENDENCY
  • Transcript

    • 1. Possibility or probability of yeasts in the ICU Do we really need to think them ? SMR. Hashemian. MD.FCCM smrhashemian@yahoo.com American College of Critical Care Medicine Fellowship Associate Professor of Critical Care /NRITLD/SBMU/Iran 1
    • 2. Epidemiology of Candida BSI Wisplinghoff H et al. Nosocomial bloodstream infection in US hospitals. Analysis of 24,179 cases From a prospective nationwide surveillance study. Clin Infect Dis 2004; 39: 309-317. • 4th most common cause of nosocomial BSI, 3rd of ICU BSI • Represents 8-11% of all nosocomial BSI • HIGHHIGH mortality + attributable mortality 15-25% for candidaemia • Non-albicans increasing, especially in cancer patients • 4th most common cause of nosocomial BSI, 3rd of ICU BSI • Represents 8-11% of all nosocomial BSI • HIGHHIGH mortality + attributable mortality 15-25% for candidaemia • Non-albicans increasing, especially in cancer patients 2
    • 3. Independent risk factors for Candida BSI Independent Variable Relative risk Odds ratio Abdominal surgery 7.3 Triple lumen CVC 5.4 Acute renal failure 4.2 Parenteral nutrition 3.6 Multiple antibiotics 12.5 Candida elsewhereCandida elsewhere 10.4 ICU > 7 days 9.8 Schelenz S. Management of candidiasis in the intensive care unit. J Antimicrob Chemother 2008; 61 Suppl 1: i31-i34. Blumberg HM et al. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. Clin Infect Dis 2001; 33: 177-86. 3
    • 4. 2008 4
    • 5. 5
    • 6. Cultured CandidaCultured Candida ColonisationColonisation Signs of sepsis ? sourceSigns of sepsis ? source ProphylacticProphylactic Presence of Risk FactorsPresence of Risk Factors Targeted Prophylactic Targeted Prophylactic Targeted Empiric Targeted Empiric Empiric (No colonisation) Empiric (No colonisation) Candida ColonisationCandida Colonisation Therapy Classification TargetedTargeted Adapted from Grenouillet F et al. J Invasive Fungal Infect 2007; 1(2): 42–9. 6
    • 7. Risk Factor Selection Underlying disease Antibiotics Colonization Fever Selection Skin or mucosa damage Infection Malignancy Diabetes Renal disease steroids Malnutrition on TPN Mechanical Ventilation > 48h Burns Instruments CV Catheter Knife
    • 8. What we know… • Early adequate therapy improves outcome – OR for death with appropriate therapy = 0.46 (p=0.05) – Therapy started day 0 mortality = 15% – Therapy started day 1 mortality = 24% – Therapy started day 2 mortality = 37% – Therapy started beyond day 2 mortality = 41% • Wrong drug at wrong time = poor outcome Parkins MD et al. J Antimicrob Chemother 2007; 60: 613-8. Garey KW et al. Clin Infect Dis 2006: 43: 25-31. Morrell M et al. Antimicrob Agents Chemother 2005: 49: 3640-3645. 8
    • 9. Diagnosis 9
    • 10. Pema´n J et al. Mycoses 2009. Saragoza R et al. Clin Vaccine Immunol 2009; 16:1527–1528. •A Spanish group has developed an antibody test against the germ-tube structure of Candida albicans cells developing when growing in culture or invading host tissue (C. albicans IFA IgG, Vircell, Spain). •Applying this test to various patients populations they have observed that patients with positive CAGTA Candida albicans Germ Tube Antibody had a better outcome than those with negative antibodies. 10
    • 11. •Direct molecular detection of Candida DNA circulating in blood has been tried for almost two decades, without much success due to the usually low yeast burden, as well as the difficulty of extracting yeast DNA and separating it from human DNA. Wallet F et al. Clin Microbiol Infect 2010; 16:774–779. 11
    • 12. This increased sensitivity implies mostly C. albicans, whereas twice more C. glabrata were detected by blood culture than by SF, but the true clinical significance of these findings has not been systematically assessed and reported. The performance of the Septifast real-time multiplex PCR 10 studies, 100 febrile episodes or samples each SEPTIFAST BLOOD CULTURE 19 positive 8 positive Bille J et al. Curr Opin Crit Care 2010 16:460–464 12
    • 13. NEWER TESTS - Another commercially available multiplex PCR test (Vyoo; SIRS-Lab, Jena, Germany) claims to detect Candida species, but no comparative trial has been published so far. - An 18S rRNA broad-range PCR following an improved DNA detection method (MolYsis; Molzym, Bremen, Germany) has shown at least twice as many positive results when compared to blood cultures. Wellinghausen N et al. J Med Microbiol 2009; 58:1106–1111. 13
    • 14. Recent approaches to reduce the delay of positivity from blood cultures: -fluorescence in-situ hybridization test (PNA FISH AdvanDX, Woburn, Massachusetts, USA) differentiates the five most prevalent species of Candida. More time consuming and expensive of FISH, allows the identification of more species of Candida than the FISH test does. PNA FISH 14
    • 15. MALDI-TOF-MS •The recent application to clinical microbiology of an old technique based on the measurement of the molecular masses of proteins and other microbial components from whole bacterial extracts. •This approach allows the identification of bacteria and yeast from isolated colonies in a few minutes with an accuracy of more than 90% when compared to conventional identification results. Seng P et al. Clin Infect Dis 2009; 49:543–551. Van Veen SQ et al. J Clin Microbiol 2010; 48:900–907. Marklein G et al. J Clin Microbiol 2009; 47:2912–2917. 15
    • 16. Is MALDI-TOF a revolution in the microbiology laboratory [Seng P et al. Clin Infect Dis 2009; 49:543–551] ? 16
    • 17. Late diagnosis with culture-based methods Slide 17 • Blood cultures lack sensitivity (<50%) • Positive cultures are usually late • Invasive tissue sampling is often problematic • Radiological signs appear often late in the course of infection
    • 18. Non-culture-based Methods Slide 18 CLINICAL MICROBIOLOGY REVIEWS, July 2002, p. 465–484
    • 19. IFI diagnostic test Guery BP et al. Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part I. Epidemiology and diagnosis. Intensive Care Med 2008 DOI 10.1007/s00134-008-1338-7 19
    • 20. 2013 20
    • 21. SSC 2013 :Rationale • The diagnosis of systemic fungal infection (usually candidiasis) in the critically ill patient can be challenging, and rapid diagnostic methodologies, such as antigen and antibody detection assays, can be helpful in detecting candidiasis in the ICU patient. • These suggested tests have shown positive results significantly earlier than standard culture methods . 21
    • 22. SSC 2013: We suggest • the use of the 1,3 β-d-glucan assay (grade 2B),mannan and anti-mannan antibody assays (grade 2C) when invasive candidiasis is in the differential diagnosis of infection. 22
    • 23. 23
    • 24. IS IA A PROBLEM IN THE ICU? 24
    • 25. Retrospective autopsy-controlled studies •127 (6.9%) of 1850 hospitalized patients had microbiologic or histopathologic evidence of aspergillosis during their ICU stay, including 89 cases (70%) in which there was not an underlying hematological malignancy. •The observed mortality rate of 80% was much higher than the mortality rate predicted on the basis of the Simplified Acute Physiology Score II (48%). Meersseman W et al. Am J Respir Crit Care Med 2004;170:621–5 •A study sought unsuspected causes of death in a ICU revealed that, among 100 autopsies, there were 15 cases of IA, of which 5 were missed before death. Roosen J et al. Mayo Clin Proc 2000; 75:562–7. 25
    • 26. WHO IS AT RISK OF DEVELOPING IA IN THE ICU? 26
    • 27. Meersseman W et al. Clin Infect Dis 2007; 45: 205-16 27
    • 28. Which diseases are associated to IA in the ICU? 28
    • 29. COPD AND ASPERGILLOSIS Lin SJ et al. Clin Infect Dis 2001; 32: 358-66 • In a review of 50 studies, COPD was the underlying condition in 26 out of 1,941 (1.3%) patients with aspergillosis • In one large study, 9% of 595 patients with IA suffered from pulmonary disease Patterson TF et al. Medicine 2000; 79: 250-60 • Steroids are believed to play a role in the emergence of IA, and some authors have investigated the correlation between the daily dose of corticosteroids and the probability of developing IA Leav BA et al. N Engl J Med 2000; 343: 586 29
    • 30. Samarakoon P et al. Chronic Resp Dis 2008; 5: 19-27 30
    • 31. Meersseman W et al. Am J Respir Crit Care Med 2008; 177:27-34 31
    • 32. What is the meaning of Aspergillus colonization? 32
    • 33. Bouza E et al. J Clin Microbiol 2005; 43:2075-9 33
    • 34. 2008 • Pulmonary Aspergillosis in Solid Organ Transplant Patients: A Report From Iran • M. Marjani, Tabarsi, K. Najafizadeh, F.R. Farokhi, B. Sharifkashani • , S. Motahari, A. Abbasi, M.R. Masjedi, D. Mansour Aspergillosis in 8 lung, 3 kidney, andAspergillosis in 8 lung, 3 kidney, and 1 heart recipient, with overall mean1 heart recipient, with overall mean age of 40.6 yearsage of 40.6 years 34
    • 35. Comparison of Serum and Bronchoalveolar Lavage Galactomannan in Diagnosing Invasive Aspergillosis in Solid-Organ Transplant Recipients •Payam Tabarsi,¹ Abdolreza Soraghi,¹ Majid Marjani,¹ Paris Zandian,¹ Parvaneh Baghaei,¹ Katayoon Najafizadeh,¹ Atoosa Droudinia,¹ Shokooh Azam Sarrafzadeh,² Pedram Javanmard,¹ Davood Mansouri¹ •17 patients were included (17 patients were included (lung, 15; heart, 1; heart-lung, 1lung, 15; heart, 1; heart-lung, 1). Probable or definite). Probable or definite invasive aspergillosis was diagnosed in 9 patientsinvasive aspergillosis was diagnosed in 9 patients. With a cutoff ≥ 0.5, serum. With a cutoff ≥ 0.5, serum galactomannan sensitivity and specificity for diagnosing invasive aspergillosis weregalactomannan sensitivity and specificity for diagnosing invasive aspergillosis were 77.18% and 100%.77.18% and 100%. •Negative predictive value and positive predictive value were 80% and 100%. TheNegative predictive value and positive predictive value were 80% and 100%. The sensitivity and specificity of bronchoalveolar lavage galactomannan for diagnosingsensitivity and specificity of bronchoalveolar lavage galactomannan for diagnosing invasive aspergillosis with cutoff of ≥ 0.5 was 100%.invasive aspergillosis with cutoff of ≥ 0.5 was 100%. 35
    • 36. Candida in ICU 36
    • 37. Candida in the ICU - Risk factors- Risk factors for candidemiacandidemia in patients in the ICU include: •the use of intravascular catheters, •parenteral nutrition •prior abdominal surgery •the use of broad-spectrum antibacterial therapy •the use of corticosteroids •AKI •a prolonged stay in the ICU, •and Candida colonization, particularly if it is multifocal. Bouza E et al. Int J Antimicrob Agents 2008;32(Suppl 2):S87–91. 37
    • 38. Diagnostic Tools Slide 38
    • 39. The Colonization Index (CI) & CCI Slide 39 Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8 Number of colonized sites Number of tested sites CI= Number of site with heavy colonization Number of tested sites CCI= CI X
    • 40. The Colonization Index (CI) & CCI Slide 40 Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8
    • 41. The Colonization Index Slide 41 Pittet D et al. Ann Surg. 1994 Dec;220(6):751-8
    • 42. Candida score The “Candida score” cut-off value is 2.5 (sensitivity 81%, specificity 74%) Leon C et al. Crit Care Med 2006; 34:730–737 42
    • 43. The Candida Score Slide 43 Leon C et al. Crit Care Med. 2006 Mar;34(3):730-7 Coefficient (β) Rounded Multifocal Candida species colonization 1.112 1 Surgery on ICU admission 0.997 1 Severe sepsis 2.038 2 Total parenteral nutrition 0.908 1 Calculation of the Candida score:
    • 44. The Candida Score Slide 44 Leon C et al. Crit Care Med. 2006 Mar;34(3):730-7 With a cut-off value of 2.5: sensitivity of 81% and a specificity of 74%, we shall only need the presence of sepsis and any one of the three other remaining risk factors or the presence of all of them together except sepsis in order to consider starting antifungal treatment for one particular patient.
    • 45. Prediction Slide 45
    • 46. 2007 Prediction rule Ostrosky-Zeichner L et al. Eur J Clin Microbiol Infect Dis 2007; 26:271-276 •Analysis of risk factors in 2,890 patients who stayed in the ICU for more than 4 days •The best prediction rule used a combination of the following factors: -any systemic Antibiotic or presence of central venous catheter and at least 2 other risk factors, including - Total Parenteral Nutrition, - major surgery, - pancreatitis, - any use of steroids and use of immunosuppressive agents. •This prediction rule exhibited a sensitivity of 34%, a specificity of 90%, a positive predictive value of 10% and a negative predictive value of 97%. •This clinical rule may therefore help clinicians to rule out invasive candididiasis. •Analysis of risk factors in 2,890 patients who stayed in the ICU for more than 4 days •The best prediction rule used a combination of the following factors: -any systemic Antibiotic or presence of central venous catheter and at least 2 other risk factors, including - Total Parenteral Nutrition, - major surgery, - pancreatitis, - any use of steroids and use of immunosuppressive agents. •This prediction rule exhibited a sensitivity of 34%, a specificity of 90%, a positive predictive value of 10% and a negative predictive value of 97%. •This clinical rule may therefore help clinicians to rule out invasive candididiasis. 46
    • 47. One of the following factors: Systemic Antibiotic Presence of CVC + at least two other risk factors Total parenteral nutrition Major surgery Pancreatitis Any use of steroids Use of immunosuppressive agents Clinical Prediction Rule Slide 47 Ostrosky-Zeichner L et al. Eur J Clin Michrobiol Infect Dis 2007, 26:271-276 Sensitivity of 34% and specificity of 90%, a positive predictive value of 10% an a negative predictive value of 97%. Mainly helps in ruling out invasive candidiasis
    • 48. Leon C et al. Crit Care Med 2009; 37:1624 –1633 Is the CS useful for discriminating between Candida colonization and invasive candidiasis in non- neutropenic critically ill patients? •Prospective, cohort, observational study on 1107 pts for >7 d in ICU •A CS>=3 selected pts at high risk for IC •IC=2.3% if CS<3 •(1–3)-Beta-D-glucan was also an independent predictor of IC (odds ratio 1.004, 95% CI 1.0 –1.007) 48
    • 49. 49
    • 50. CS,,,Cristobal Leon 2009 CCM Leon C et al. Crit Care Med 2009; 37:1624 –1633 50
    • 51. Leon C et al. Crit Care Med 2009; 37:1624 –1633 CS,,,Cristobal Leon 2009 CCM 51
    • 52. 2011 52
    • 53. 53
    • 54. 2011 NMC rule Nebraska 54
    • 55. 55
    • 56. 56
    • 57. 57
    • 58. 58
    • 59. NMC 59
    • 60. SAT 2012 CCM 60
    • 61. 61
    • 62. 62
    • 63. 63
    • 64. 7.5% SAT,2/3 no IFI 64
    • 65. L.Ostrosky.Z (Purple)KEY 65
    • 66. 66
    • 67. Predictors of SAT • included • smaller hospital size, an onsite transplant • program, and a perceived high incidence • of Candida infections in the previous year. • Although there was a trend for improved • adjusted 28-day survival, the authors • failed to find any difference in outcome • for the patients who received SAT. 67
    • 68. 36 ICU Spain,France,Argentina 2012 68
    • 69. 69
    • 70. Tendency • 38 candidemias were diagnosed in 1,107 patients Patients with and without candidemia had an ICU crude mortality of 52.6% versus 20.6% (P < 0.001) 70
    • 71. Propensity score matching analysis(PSM) 71
    • 72. Italy 2013 ICU-acquired candidemia in critically illICU-acquired candidemia in critically ill patients is not associated with an increasepatients is not associated with an increase in either ICU or hospital mortality.in either ICU or hospital mortality. 72
    • 73. 73
    • 74. 2009 74
    • 75. 2010 75
    • 76. Calibration model 76
    • 77. 77
    • 78. Modification 2013 Modification of Acute Physiology and Chronic Health Evaluation II score through recalibration of risk prediction model in critical care patients of a respiratory disease referral center Ali A. Velayati, Yadollah Mehrabi, Golnar Radmand,1 Ali A Khadem Maboudi,1 Hamid R. Jamaati,2 A. Shahbazi,3 Seyed A. Mohajerani,3 and Seyed M R. Hashemian Modification of Acute Physiology and Chronic Health Evaluation II score through recalibration of risk prediction model in critical care patients of a respiratory disease referral center Ali A. Velayati, Yadollah Mehrabi, Golnar Radmand,1 Ali A Khadem Maboudi,1 Hamid R. Jamaati,2 A. Shahbazi,3 Seyed A. Mohajerani,3 and Seyed M R. Hashemian 78
    • 79. 79
    • 80. Probability 80
    • 81. 81
    • 82. Fungal Infection Risk Evaluation (FIRE) 2013 Better targeting of antifungal prophylaxis to improve care and outcomes…
    • 83. FIRE dataset Dataset defined in five sections: • Patient details • Pre-admission • First 24 hours • By end of calendar day 3 • Outcomes 83
    • 84. FIRE dataset – Outcomes – Fungal colonisation – Invasive fungal disease – Use of systemic antifungal drugs – Use of topical antifungal drugs – Surgery (first during unit stay) 84
    • 85. 85
    • 86. Economic modelling to assess the cost-effectiveness of prophylaxis based on the risk models for invasive Candida infection • The decision model was populated with estimates of positive predictive value (the proportion of those identified as high risk who subsequently developed invasive Candida infection) and negative predictive value (the proportion of those identified as low risk who did not subsequently develop invasive Candida infection) 86
    • 87. Data collection for risk factors and outcomes of invasive fungal disease • Data on 60,778 admissions to 96 adult general critical care units were collected between July 2009 and March 2011. The reliability study identified substantial over-reporting of IFD in the original data submissions, suggesting difficulty in correctly applying the IFD definitions. 87
    • 88. 88

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