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Medical and Pathogenic Mycology Fungal ABC’s

Medical and Pathogenic Mycology Fungal ABC’s. Medical Mycology: Clinical Classification. Yeasts Systemic disease, pulmonary disease absent or subclinical Dimorphic fungi Primary pulmonary disease with dissemination prominent part of disease Molds

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Medical and Pathogenic Mycology Fungal ABC’s

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  1. Medical and Pathogenic Mycology Fungal ABC’s

  2. Medical Mycology: Clinical Classification • Yeasts • Systemic disease, pulmonary disease absent or subclinical • Dimorphic fungi • Primary pulmonary disease with dissemination prominent part of disease • Molds • Primary pulmonary disease with dissemination less common

  3. Invasive Mold Infections • Immunosuppressed patients only • Pulmonary infection by inhalation of airborne spores with subsequent dissemination • Very aggressive, destructive • Aspergillus most common (>80%) • Aspergillus fumigatus most common species • Others • Rhizopus, Absidia, Mucor (Zygomycetes) • Penicilllium • Pseudallescheriaboydii

  4. Aspergillus fumigatus • Ubiquitous mold • Found on decaying material • Produces large amount of airborne conidia • On average at 100 to 1000 conidia are inhaled daily

  5. A B C D Alveolar Infection E Angioinvasion Dissemination

  6. Invasive Aspergillosis Risk Groups - Risk Factors • Hematologic malignancy • HSCT (especially allogeneic) • Host variables (age, underlying disease) • Transplant factors (source of stem cells) • Late complications (GVHD, corticosteroids, secondary neutropenia) • Solid-organ transplant • Advanced HIV disease SOT = solid organ transplant Marr KA et al. Blood 2002;100:4358-66; Lin SJ et al. Clin Infect Dis. 2001;32:358-66.

  7. Time to Onset of IFI After HSCT # of UFU’s PG Pappas: Transplant Associated Infection Surveillance Network

  8. Invasive Mycotic Diseases 1980 – 1997 Trends in Mortality Candidiasis Other Mycoses +329% Rate per 100,000 population Aspergillosis +357% Year McNeil MM et al. Clin Infect Dis. 2001;33:641-7.

  9. Invasive Aspergillosis in CanadaEmerging Epidemiology:

  10. The Diagnostic Challenge – IA Ascioglu S et al. Clin Infect Dis. 2002;34:7-14.

  11. Autopsy-Proven IFD ConfirmsUnder-Diagnosis of IFD • Two-site autopsy study of 97 allogeneic stem cell recipients IFI Deaths Ante Mortem Screening: (1) Regular galactomannan testing (2) CT scans Sinko et al. Transpl Infect Dis 2008: 10: 106 -109

  12. Diagnostic Methods Perlroth J et al. Med Mycol. 2007;45:321-46.

  13. Galactamannan (GM) Assay • GM is a carbohydrate constituent of the fungal cell wall and is released during hyphal growth • Commercial, FDA approved sandwich EIA for detection of circulating A. fumigatus GM • Can be used on serum or BAL fluid • Cutoff for positive is an index of 0.5 (serum) • May be detected 5-8 days before symptoms

  14. Utility and Limitations • Serum • FDA literature - Sensitivity 80.7%, Specificity 89.2% • Meta analysis - Sensitivity 73% and Specificity 81% • Most useful in serial sampling • Highest sensitivity in neutropenic patients • BAL • Cutoff 0.5 – Sensitivity 100%, Specificity 78% • Cutoff 2.0 – Sensitivity 100%, Specificity 93.2% • GM > 2 associated with a 4.68 CHR of death

  15. Protocol for MUHC 1. Presumptive diagnosis of IA: Testing on request of adult inpatients with at least one risk factor for IA and at least one clinical criteria consistent with IA 2. Pre-emptive screening: Routine screening of all high risk inpatients on hematology wards Sera will be collected three times per week (Mon-Wed-Fri) Assays will be run twice weekly (Tues-Thurs).

  16. Case • 51 year old woman • April 2010 AML • Induced with FLAG-IDA • CR • March 2011 • Allo HSCT from brother

  17. Case • Severalcomplications • GVHD (Grade III) – liver skin and bowel • CMV positive April 2011 until Dec 2011 • Multiple antivirals used including gancyclovir, foscarnet and cidofivir • EBV PCR positive April 2011, • Rituximab given Dec 2011

  18. Case • Admitted Dec 2011 with fevers 7 d after rituximab • S. bovisbacteremia (Rx Ceftriaxone) • RSV + in nasal swab – (Rx Ribivarin) • HHV-6 PCR positive on blood • CMV colitis • Relative stable by Jan 1 2012 and afebrile

  19. 4 Days

  20. Days

  21. Voriconazole

  22. McGill University: Incidence of IA AML and Allogeneic Stem Cell Transplant patients Pre-galactoamman Incidence of IA

  23. McGill University: Incidence of IA AML and Allogeneic Stem Cell Transplant patients Post-galactomannan Incidence of IA

  24. Rates of Invasive Aspergillosis

  25. Invasive Fungal Infection Management

  26. Antifungal Agents - Sites of Action Ampho B Azoles Echinocandins ß-1, 3 glucanpolysaccharide Ergosterol Cell Membrane Phospholipid bilayer Adapted from Metcalf SC, Dockrell DH. J Infect. 2007;55:287-99.

  27. Drug Classes and Agents *Not yet approved ABLC = Amphotericin B lipid complex; ABCD = Amphotericin B colloidal dispersion; L-AMB: Liposomal amphotericin B Metcalf SC, Dockrell DH. J Infect 2007;55:287-299; Petrikkos G, Skiada A. Internat J Antimicrob Agents 2007;30:108-117

  28. IFI Management Disease progression No disease Markers Signs & symptoms Full-blown disease Sequelae Prophylactic Asymptomatic high-risk patient Asymptomatic + colonization OR novel diagnostic Preemptive Empirical High risk: Antibiotic + fever Evidence of infection + clinical disease Therapy Wingard JR. Best Pract Res Clin Haematol 2007;20:99-107; Bow EJ. Hematol. 2006;1:361-7.

  29. IA Primary Therapy Voriconazole vs. Amphotericin B Survival at 12 weeks 70.8% Patients Surviving (%) 57.9% P=0.02 Weeks No. at Risk Voriconazole 144 131 125 117 111 107 102 Amphotericin B 133 117 99 87 84 80 77 Herbrecht R et al. N Engl J Med. 2002;347:408-15.

  30. Voriconazole Caveats No activity against Zygomycetes Erratic pharmacokinetics Drug interactions Hepatotoxicity Visual toxicity Cumulative Incidence (%) Siwek GT et al. Clin Infect Dis. 2004;39:584-7; Scott LJ, Simpson D. Drugs 2007;67:269-298

  31. IA Salvage Therapy Caspofungin 83 evaluable patients refractory to or intolerant of Ampho B, lipid formulations or triazoles 86% refractory, 15% intolerant 48% hematologic malignancy, 25% HSCT 45% favourable response, including 50% with pulmonary aspergillosis 23% with disseminated aspergillosis Excellent safety profile Maertens J et al. Clin Infect Dis. 2004;39:1563-71.

  32. Early Intervention is Associated with Lower Mortality Retrospective analysis of the timing of empiric antifungal treatment for 33 cases of invasive aspergillosis between 1987 and 1992 Von Eiff et al. Respiration.1995;62:341-347.

  33. Initiation of Therapy Early Therapy  Better Outcomes "Clinical trial data indicate rapidity of therapy initiation is an important and independent determinant of outcome." M. Morrell Morrell M et al. Antimicrob Agents Chemother. 2005;49:3640-5.

  34. IFI Management Disease progression No disease Markers Signs & symptoms Full-blown disease Sequelae Prophylactic Asymptomatic high-risk patient Asymptomatic + colonization OR novel diagnostic Preemptive Empirical High risk: Antibiotic + fever Evidence of infection + clinical disease Therapy Bow EJ. Hematol. 2006;1:361-7.

  35. Empirical Therapy Pros High mortality Difficulties in diagnosis Treat undetected infection May reduce systemic mycoses (Pizzo) May reduce mortality (EORTC) Cons Over-treatment Fever is non-specific Side-effects and cost Difficulties in diagnosis Infected patients: too little treatment Uninfected patients: too much treatment • Treat all neutropenic patients with persistent fever despite broad-spectrum antibiotics Wingard JR. Best Pract Res Clin Haematol 2007;20:99-107; Bow EJ. Hematol 2006;1:361-367; Pizzo Am J Med. 1982:72;101-11; EORTC Am J Med. 1989;86:668-72.

  36. Early Trials • Pizzo Am J Med 1982 • First comparative evaluation of empiric antifungal therapy • Enrollment Criteria • Fever for 7d after antimicrobials started, PMN<500 • Predominately pediatric population (mean age 16) • Randomized to stopping all abts, no change or 0.5mg/kg/d AmB

  37. Pizzo - Outcomes * Minimal renal toxicity

  38. EORTC Trial • Larger study of empiric AmB use in febrile neutropenics • Enrollment • Adult population • Fever for 4 days after antibacterials started • PMN<1000 • Randomized to empiric AmB 0.6mg/kg/d or 1.2mg/kg/2d

  39. EORTC - Outcomes

  40. Empirical Therapy Voriconazole or Caspofungin vs L-AMB Walsh T et al. N Engl J Med. 2002;346:225-35; N Engl J Med. 2004;351:1391-1402.

  41. Empiric therapy - summary • Cons • Original evidence for efficacy is weak • Fever is not specific and not sensitive in hematology population • 50% of GM+ patients are afebrile • Institution of highly active mold prophylaxis reduces mortality, pulmonary infiltrates but NOT fever • Overall success in high risk patients is sub-optimal • So what else can we do?

  42. IFI Management Disease progression No disease Markers Signs & symptoms Full-blown disease Sequelae Prophylactic Asymptomatic high-risk patient Asymptomatic + colonization OR novel diagnostic Preemptive Empirical High risk: Antibiotic + fever Evidence of infection + clinical disease Therapy Bow EJ. Hematol. 2006;1:361-7.

  43. Preemptive Therapy Incorporation of Diagnostic Tests High-risk hematology patients (all received Candida prophylaxis, fluconazole 400 mg/day) Daily GM monitoring and clinical evaluation >5 days of unexplained neutropenic feverrefractory toantibiotics or relapsing New infiltrate on chest X-ray or signs/symptoms of invasive mycosis Positive culture or microscopy (molds) OD index 2 x ≥ 0.5 Thoracic CT scan (± CT sinus) Thoracic CT & BAL Characteristic of invasivemycosis: ‘halo-sign’ Atypical lesion Normal Bronchoscopy with BAL - + Broad-spectrumantifungal therapy Continued monitoring No antifungal therapy Maertens J et al. Clin Infect Dis. 2005;41:1242-50.

  44. Empirical vs Preemptive antifungal therapy in high risk neutropenic patients Overall survival Proven and probable IFI p=ns *p<0.02 Cordonnier et al. CID 2009

  45. PreemptiveTherapyDoes Not Reduce IA Mortality

  46. If earlier is better… Is prevention best?

  47. IFI Management Disease progression No disease Markers Signs & symptoms Full-blown disease Sequelae Prophylactic Asymptomatic high-risk patient Asymptomatic + colonization OR novel diagnostic Preemptive Empirical High risk: Antibiotic + fever Evidence of infection + clinical disease Therapy Bow EJ. Hematol. 2006;1:361-7.

  48. Fluconazole Prophylaxis in HSCT • Evidence for Long-term Survival Related and Unrelated Donor Transplants Fluconazole 400 mg/d Survival Probability P = .0018 Placebo Years After Transplant HSCT indicates hematopoietic stem cell transplant. Marr KA, et al. Blood. 2000;96:2055-2061.

  49. Overall Treatment Success • Micafungin vs. Fluconazole Proportion of patients with treatment success P = 0.025, by the log rank test micafungin (n = 425) Fluconazole (n = 457) Time to treatment failure (days since first dose of study drug) Adapted from van Burik JA, et al: Clin Infect Dis 2004; 39(10):1407-16.

  50. Voriconazole vs. Fluconazole p=0.49 p=0.12 Subjects: 600 standard-risk allogeneic blood and marrow transplant patients *Proven + probable + presumptive Adapted from Wingard JR, et al: Blood epub 2010

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