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Medical and Pathogenic Mycology Fungal ABC’s Medical and Pathogenic Mycology Fungal ABC’s.

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Presentation on theme: "Medical and Pathogenic Mycology Fungal ABC’s Medical and Pathogenic Mycology Fungal ABC’s."— Presentation transcript:

1 Medical and Pathogenic Mycology Fungal ABC’s 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 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 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  Pseudallescheria boydii 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  Pseudallescheria boydii Invasive Mold Infections

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 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 CD E Alveolar Infection Angioinvasion Dissemination

6 Marr KA et al. Blood 2002;100: ; Lin SJ et al. Clin Infect Dis. 2001;32: SOT = solid organ transplant 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 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 Invasive Aspergillosis Risk Groups - Risk Factors

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

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

9 Invasive Aspergillosis in Canada Emerging Epidemiology:

10 Ascioglu S et al. Clin Infect Dis. 2002;34:7-14. The Diagnostic Challenge – IA Proven Histopathology and/or Growth in culture from tissue biopsy or aspirate from a sterile site Probable Presence of 1 host factor criterion, 1 clinical feature and microbiological evidence (includes galactomannan) Culture from sputum or BAL in immunocompromised patient with clinical evidence of infection “The problem of uncertainty cannot be disregarded as if it does not exist…” EORTC International Consensus Possible At least 1 host factor criterion  Neutropenia  Persistent fever despite antibiotics in high-risk patients  Signs and symptoms of GVHD  Prolonged corticosteroid use

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

12 Perlroth J et al. Med Mycol. 2007;45: Diagnostic Methods CT Scan  Nodules or patchy consolidations  Halo sign: attenuated area around a nodule Specific to IA? - in the setting of immunocompromise Sensitivity varies with timing relative to diagnosis (high early) (1,3)-ß-D-glucan assay  Excellent negative predictive value  False positives: Albumin Immunoglobulin Hemodialysis Galactomannan assay  Sensitivity 0.73, specificity 0.81 (proven IA)  False positives: Lowered threshold for test positivity Bifidobacterium lipoglycan Concurrent use of ß-lactam antibiotics, particularly piperacillin-tazobactam PCR detection of fungal DNA  Sensitivity 100% for IA (preceding symptoms by a median of 2 days)  Requires further standardization and validation

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 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 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 51 year old woman April 2010 AML  Induced with FLAG-IDA  CR March 2011  Allo HSCT from brother

17 Case Several complications  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 Several complications  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. bovis bacteremia (Rx Ceftriaxone)  RSV + in nasal swab – (Rx Ribivarin)  HHV-6 PCR positive on blood  CMV colitis  Relative stable by Jan and afebrile  Admitted Dec 2011 with fevers 7 d after rituximab  S. bovis bacteremia (Rx Ceftriaxone)  RSV + in nasal swab – (Rx Ribivarin)  HHV-6 PCR positive on blood  CMV colitis  Relative stable by Jan and afebrile

19 Days 4

20

21 Voriconazole

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

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

24 Rates of Invasive Aspergillosis CentrePopulation IA Incidence (%) Maisonneuve Rosemont Hospital Allogeneic HSCT15 Acute Leukemia8.9 Vancouver General Hospital Allogeneic HSCT18.8 Hotel Dieu QuebecAML17.8

25 Invasive Fungal Infection Management

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

27 Drug Classes and Agents Polyenes Amphotericin B (AMB) Lipid-based formulations  ABLC  ABCD  L-AMB Expanded-spectrum azoles Voriconazole Posaconazole Ravuconazole* Azoles Fluconazole Itraconazole Echinocandins Caspofungin Micafungin Anidulafungin *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: ; Petrikkos G, Skiada A. Internat J Antimicrob Agents 2007;30:

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

29 Herbrecht R et al. N Engl J Med. 2002;347: % 57.9% Survival at 12 weeks Voriconazole vs. Amphotericin B IA Primary Therapy Patients Surviving (%) Weeks No. at Risk Voriconazole Amphotericin B No. at Risk Voriconazole Amphotericin B P=0.02

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

31 Maertens J et al. Clin Infect Dis. 2004;39: 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

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

33 Morrell M et al. Antimicrob Agents Chemother. 2005;49: 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

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

35 Wingard JR. Best Pract Res Clin Haematol 2007;20:99-107; Bow EJ. Hematol 2006;1: ; Pizzo Am J Med. 1982:72;101-11; EORTC Am J Med. 1989;86: Treat all neutropenic patients with persistent fever despite broad-spectrum antibiotics 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

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 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 No Δ+AmBD/C Rx # pts Candida4(3)01 Mold211 Infectious Complications7(6)29 Survival Time to defervesce7-83-5d11-12d * 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 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 No Δ+AmB # pts6468 Candida41 Mold20 Survival79%84% Response (fever)5369

40 Walsh T et al. N Engl J Med. 2002;346:225-35; N Engl J Med. 2004;351: Empirical Therapy VOR N=415 L-AMB N=422 Point Estimate for Percent Difference (95% CI) Overall response no. (%) 108 (26%) 129 (30.6%) -4.5 (-10.6 to 1.6) P=NS Breakthrough fungal infection 8 (1.9%) 21 (5.0%)P=0.02 Voriconazole or Caspofungin vs L-AMB CAS N=556 L-AMB N=539 Point Estimate for Percent Difference (95% CI) Overall response no. (%) 190 (33.9%) 181 (33.7%) 0.2 (-5.6 to 6.0) Non-inferiority Absence of breakthrough fungal infection 29 (5.2%) 24 (4.5%) P=0.56

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

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

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

45 Preemptive Therapy Does Not Reduce IA Mortality

46 If earlier is better… Is prevention best?

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

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

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

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

51 Voriconazole vs. Itraconazole: Improvit 489 allogeneic stem cell transplant patients

52 N = 602 Chemotherapy & prophylaxis Chemotherapy & prophylaxis (if needed) Day 100 postrandomization Posaconazole (n = 304) Fluconazole or Itraconazole (n = 298) Primary end point time period Secondary end point time period Cornely OA et al. N Engl J Med 2007;356: Study Design Antifungal Prophylaxis: Neutropenia Posaconazole vs Fluconazole / Itraconazole

53 † † * P<0.001; † P= Treatment Phase 100 Day Period After Randomization Primary Endpoint: Prevention of IFI Posaconazole vs Flu/Itra Cornely OA et al. N Engl J Med 2007;356: Fluconazole n=304 Posaconazole n=298 Fluconazole n=304 Posaconazole n=298

54 Probability of Death Days After Randomization P =.04* Posaconazole Fluconazole or Itraconazole Death From Any Cause *Estimated using log-rank statistics. Censoring time is the minimum of the last contact date and day 100. Cornely OA, et al. N Engl J Med 2007;356: % 14% 33% relative reduction in mortality Antifungal Prophylaxis: Neutropenia

55 N = 600 First dose Last dose Last dose + 7 days Posaconazole (n = 301) Posaconazole (n = 301) (n = 299) Fluconazole (n = 299) Fluconazole Secondary end point time period Primary end point time period Day 112 Day months Follow-up Ullmann AJ et al. New Engl J Med. 2007;356: Posaconazole vs Fluconazole Antifungal Prophylaxis: GVHD Study Design

56 * P=0.07; † P= 0.006; ‡ P=0.004; § P=0.001 Ullmann AJ et al. New Engl J Med. 2007;356: Antifungal Prophylaxis: GVHD † † Fixed Treatment Period Exposure Period Number of IFI (Proven/Probable) ‡ ‡ § § Fluconazole n=304 Posaconazole n=298 Fluconazole n=304 Posaconazole n=298 Primary Endpoint: Prevention of IFI

57 Deaths - By Cause Fluconazole (N=301) Posaconazole (N=299) Fluconazole (N=301) Posaconazole (N=299) ** * Ullmann AJ et al. New Engl J Med. 2007;356: Antifungal Prophylaxis: GVHD *

58 Comparative Efficacy in Prophylaxis Retrospective review: 573 AML inductions over 12 years Ananda-Rajah et al; Hematologica 2012;97(3)

59 De Pauw BE. N Engl J Med. 2007;356: Prophylaxis:  What are the trade-offs in the long-term ? Cost and potential resistance Incidence within an institution (number-needed- to-treat)

60 Resistance Intrinsic barrier to resistance for molds  Infections acquired in the community  Not transmitted person to person  No selection pressure on the environmental reservoir Breakthroughs in 3 years of posaconazole prophylaxis Intrinsic resistance only  1 case of MDR Fusarium  1 case of Aspergillus calidoustus Intrinsic barrier to resistance for molds  Infections acquired in the community  Not transmitted person to person  No selection pressure on the environmental reservoir Breakthroughs in 3 years of posaconazole prophylaxis Intrinsic resistance only  1 case of MDR Fusarium  1 case of Aspergillus calidoustus

61 Costs  Costs  Prophylactic agent  Benefits  Reduced empiric antifungal use or screening protocols  Reduction in associated costs (ICU stay, other drugs/fever workup)  Reduction in mortality  Sensitive to NNT – linked to local epidemiology  Costs  Prophylactic agent  Benefits  Reduced empiric antifungal use or screening protocols  Reduction in associated costs (ICU stay, other drugs/fever workup)  Reduction in mortality  Sensitive to NNT – linked to local epidemiology

62 FUNGAL PROPHYLAXIS AML/MDS induction Stem cell transplant GVHD FLUCONAZOLE Allo transplant: 400 mg PO/IV QD Autologous transplant: 200 mg IV/PO QD GVHD: mg PO/IV QD (adjust with renal function, check for interactions) POSACONAZOLE 200 mg PO TID (Check for interactions, optimize absorption**) AML/MDS Induction (this is the only indication for posaconazole) YES NO **Absorption: Avoid acid suppressants; give with or after high fat meal or with nutritional supplement MUHC Algorithm – Prophylaxis

63 MUHC Algorithm – Preemptive Autologous HSCT, Consolidation, Allo HSCT pre-engraftment


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