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

Primary pulmonary disease with dissemination less common

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 Pseudallescheria boydii

Aspergillus fumigatus

• • • •

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

Alveolar Infection Angioinvasion A B C D E Dissemination

Invasive Aspergillosis

Risk Groups - Risk Factors

18% BMT/Heme SOT AIDS/Immune Pulm 7% 63% • • • • Hematologic malignancy 12% 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.

Time to Onset of IFI After HSCT

120 100 80 IA Candidiasis Fusarium Other mould PCP Unspec. mould Zygomycetes 60 40 20 0 Early Onset (0-30 days) Intermediate Onset (30-60 days) Late Onset (90+ days) PG Pappas: Transplant Associated Infection Surveillance Network

Trends in Mortality

Invasive Mycotic Diseases 1980 – 1997

Candidiasis

0.6

Candidiasis Aspergillosis Other Mycoses

Other Mycoses +329%

0.4

Aspergillosis +357%

0.2

0.0

1981 1986 Year 1991 1996 McNeil MM et al.

Clin Infect Dis

. 2001;33:641-7.

Invasive Aspergillosis in Canada Emerging Epidemiology:

The Diagnostic Challenge – IA

Proven

• • Histopathology and/or Growth in culture from tissue biopsy or aspirate from a sterile site

Probable Possible

• • 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

• At least 1 host factor criterion     Neutropenia Persistent fever despite antibiotics in high-risk patients Signs and symptoms of GVHD Prolonged corticosteroid use Ascioglu S et al.

Clin Infect Dis.

2002;34:7-14.

Autopsy-Proven IFD Confirms Under-Diagnosis of IFD

•

Two-site autopsy study of 97 allogeneic stem cell recipients

12 Ante Mortem 10 10 Post Mortem 8 6 6 4 2 0 4 3 2 2 1 Total Aspergillosis Candidiasis 0 Mucromycosis

Ante Mortem Screening:

(1) Regular galactomannan testing (2) CT scans Sinko et al. Transpl Infect Dis 2008: 10: 106 -109

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 Perlroth J et al.

Med Mycol.

2007;45:321-46.

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

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

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).

Case 51 year old woman April 2010 AML

  Induced with FLAG-IDA CR March 2011  Allo HSCT from brother

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

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 1 2012 and afebrile

Days 4

Days

Voriconazole

McGill University: Incidence of IA

AML and Allogeneic Stem Cell Transplant patients Pre-galactoamman

50% 40% 30% 20% 10% 0% All Possible Proven and Probable

McGill University: Incidence of IA

AML and Allogeneic Stem Cell Transplant patients Post-galactomannan

50% 40% 30% 20% 10% 0% Pre-GM Post-GM All Possible Proven and Probable

Rates of Invasive Aspergillosis

Centre Maisonneuve Rosemont Hospital Population Allogeneic HSCT IA Incidence (%) 15 Acute Leukemia 8.9

Vancouver General Hospital Hotel Dieu Quebec Allogeneic HSCT AML 18.8

17.8

Invasive Fungal Infection

Management

Antifungal Agents - Sites of Action

ß-1, 3 glucan polysaccharide Ergosterol Cell Membrane Phospholipid bilayer Azoles Adapted from Metcalf SC, Dockrell DH.

J Infect.

2007;55:287-99.

Drug Classes and Agents

Polyenes

• Amphotericin B (AMB) • Lipid-based formulations  ABLC  ABCD  L-AMB

Azoles

• • Fluconazole Itraconazole

Expanded-spectrum azoles

• • • Voriconazole Posaconazole Ravuconazole*

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;55:287-299; Petrikkos G, Skiada A. Internat J Antimicrob Agents 2007;30:108-117

IFI Management

No disease Markers Signs & symptoms Full-blown disease Sequelae

Prophylactic

Asymptomatic high-risk patient

Preemptive

Asymptomatic + colonization OR novel diagnostic

Empirical Therapy

High risk: Antibiotic + fever Evidence of infection + clinical disease Wingard JR.

Best Pract Res Clin Haematol

2007;20:99-107; Bow EJ.

Hematol.

2006;1:361-7.

IA Primary Therapy

Voriconazole vs. Amphotericin B

Survival at 12 weeks 100 80 60 40 20 0 0

P=0.02

2 No. at Risk Voriconazole Amphotericin B 144 133 131 117 4 125 99

70.8% 57.9%

6 Weeks 117 87 8 10 12 111 84 107 80 102 77 Herbrecht R et al.

N Engl J Med.

2002;347:408-15.

Voriconazole

12

Caveats

 No activity against Zygomycetes  Erratic pharmacokinetics    Drug interactions Hepatotoxicity Visual toxicity 10 8 6 4 2 Aspergillus Zygomycetes 0 Pre Voriconazole Post Voriconazole Siwek GT et al.

Clin Infect Dis.

2004;39:584-7; Scott LJ, Simpson D. Drugs 2007;67:269-298

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.

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

90 80 70 60 50 40 30 20 10 0 <10 days >11 days Time from onset of pneumonia to initiation of antifungal therapy

Von Eiff et al.

Respiration

. 1995;62:341-347.

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.

IFI Management

No disease Markers Signs & symptoms Full-blown disease Sequelae

Prophylactic

Asymptomatic high-risk patient

Preemptive

Asymptomatic + colonization OR novel diagnostic

Empirical

High risk: Antibiotic + fever

Therapy

Evidence of infection + clinical disease Bow EJ.

Hematol.

2006;1:361-7.

Empirical Therapy

• Treat all neutropenic patients with persistent fever despite broad-spectrum antibiotics

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 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.

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 - Outcomes

# pts Candida Mold Infectious Complications Survival Time to defervesce

No Δ

16 4(3) 2 7(6) 11 7-8

+AmB

18 0 1 2 15 3-5d * Minimal renal toxicity

D/C Rx

16 1 1 9 11 11-12d

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

EORTC - Outcomes

# pts Candida Mold Survival Response (fever) No Δ

64 4 2 79% 53

+AmB

68 1 0 84% 69

Empirical Therapy

Voriconazole or Caspofungin vs L-AMB

Overall response no. (%) Breakthrough fungal infection

VOR N=415

108 (26%) 8 (1.9%)

L-AMB N=422

129 (30.6%) 21 (5.0%)

Point Estimate for Percent Difference

(95% CI)

-4.5 (-10.6 to 1.6)

P

=NS

P

=0.02

Overall response no. (%) Absence of breakthrough fungal infection

CAS N=556

190 (33.9%) 29 (5.2%)

L-AMB N=539

181 (33.7%) 24 (4.5%)

Point Estimate for Percent Difference

(95% CI)

0.2 (-5.6 to 6.0) Non-inferiority

P

=0.56

Walsh T et al.

N Engl J Med.

2002;346:225-35;

N Engl J Med.

2004;351:1391-1402.

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?

IFI Management

No disease Markers Signs & symptoms Full-blown disease Sequelae

Prophylactic

Asymptomatic high-risk patient

Preemptive

Asymptomatic + colonization OR novel diagnostic

Empirical

High risk: Antibiotic + fever

Therapy

Evidence of infection + clinical disease Bow EJ.

Hematol.

2006;1:361-7.

Preemptive Therapy

Incorporation of Diagnostic Tests

High-risk hematology patients (all received

Candida

prophylaxis, fluconazole 400 mg/day) Daily GM monitoring and clinical evaluation OD index 2 x ≥ 0.5

Thoracic CT & BAL Broad-spectrum antifungal therapy >5 days of unexplained neutropenic fever refractory to antibiotics or relapsing Characteristic of invasive mycosis: ‘halo-sign’ New infiltrate on chest X-ray or signs/symptoms of invasive mycosis Thoracic CT scan ( ± CT sinus) Atypical lesion Positive culture or microscopy (molds) Normal + Bronchoscopy with BAL Continued monitoring No antifungal therapy Maertens J et al.

Clin Infect Dis.

2005;41:1242-50.

Empirical vs Preemptive antifungal therapy in high risk neutropenic patients

100% 80% 60% 40% Overall survival 97.0% 95.0% 20% 0% Empirical, n=150 Pre-emptive, n=143

p=ns

20% Proven and probable IFI 15% 10% 9.0% 5% *2.7% 0% Empirical, n=150 Pre-emptive, n=143

*p<0.02

Cordonnier et al. CID 2009

Preemptive Therapy Does Not Reduce IA Mortality

100 80 60 40 20 0

MRH MUHC Average

If earlier is better… Is prevention best?

IFI Management

No disease Markers Signs & symptoms Full-blown disease Sequelae

Prophylactic

Asymptomatic high-risk patient

Preemptive

Asymptomatic + colonization OR novel diagnostic

Empirical

High risk: Antibiotic + fever

Therapy

Evidence of infection + clinical disease Bow EJ.

Hematol.

2006;1:361-7.

Fluconazole Prophylaxis in HSCT

•

Evidence for Long-term Survival

Related and Unrelated Donor Transplants

1.00

0.75

Fluconazole 400 mg/d 0.50

P = .0018

0.25

Placebo 0.00

0 1 2 3 4 5 6 Years After Transplant HSCT indicates hematopoietic stem cell transplant.

7 8 9 Marr KA, et al. Blood. 2000;96:2055-2061.

Overall Treatment Success

•

Micafungin vs. Fluconazole

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0

P

= 0.025, by the log rank test micafungin (

n

= 425) Fluconazole (

n

= 457) 10 20 30 40 50 60 Time to treatment failure (days since first dose of study drug) 70 Adapted from van Burik JA, et al: Clin Infect Dis 2004; 39(10):1407-16.

60 40 20

Voriconazole vs. Fluconazole

p=0.49

80

p=0.12

Voriconazole Fluconazole 0 Survival Breakthroughs Hepatotoxicity

Subjects:

600 standard-risk allogeneic blood and marrow transplant patients *Proven + probable + presumptive Adapted from Wingard JR, et al: Blood epub 2010

Voriconazole vs. Itraconazole: Improvit

489 allogeneic stem cell transplant patients

100 80 a g e P e r c e n t 60 40 20 0 Voriconazole Itraconazole

Antifungal Prophylaxis: Neutropenia

Posaconazole vs Fluconazole / Itraconazole

Study Design

Posaconazole (n = 304) N = 602 Chemotherapy & prophylaxis Chemotherapy & prophylaxis (if needed) Fluconazole or Itraconazole (n = 298) Day 100 postrandomization Primary end point time period Secondary end point time period Cornely OA et al.

N Engl J Med

2007;356:348-59.

40 35 30 25 20 15 10 5 0

Posaconazole vs Flu/Itra

Primary Endpoint: Prevention of IFI

Treatment Phase 100 Day Period After Randomization

Fluconazole n=304 Posaconazole n=298 )2%( 7 25 (8%) 2 (1%) )7%( 20 )5%( 14 33 (11%) † All IFIs 4 (1%) )9%( 26 All IFIs* *

P

<0.001; †

P

= 0.003

Aspergillosis Aspergillosis Cornely OA et al.

N Engl J Med

2007;356:348-59.

Antifungal Prophylaxis: Neutropenia

Death From Any Cause

0.30

Posaconazole Fluconazole or Itraconazole 0.25

21%

0.20

P = .04*

0.15

14%

0.10

0.05

33% relative reduction in mortality

0.00

0 20 40 60 Days After Randomization *Estimated using log-rank statistics.

Censoring time is the minimum of the last contact date and day 100.

80 100 Cornely OA, et al.

N Engl J Med

2007;356:348-359

Antifungal Prophylaxis: GVHD

Posaconazole vs Fluconazole

Study Design

N = 600

Posaconazole (n = 301)

First dose

(n = 299) Fluconazole

Last dose Last dose + 7 days Secondary end point time period Primary end point time period Day 112 Follow-up Day 112 +2 months Ullmann AJ et al.

New Engl J Med.

2007;356:335-47.

20 15 10 5 0 40 35 30 25

Antifungal Prophylaxis: GVHD

Primary Endpoint: Prevention of IFI

Fixed Treatment Period Exposure Period

Fluconazole n=304 Posaconazole n=298 )5%( 16 27 (9%) 7 (2%) )7%( 21 )2%( 7 22 (8%) 3 (1%) )6%( 17 All IFIs* Aspergillosis † All IFIs ‡ *

P

=0.07; †

P

= 0.006; ‡

P

=0.004; §

P

=0.001

Aspergillosis § Ullmann AJ et al.

New Engl J Med.

2007;356:335-47.

Antifungal Prophylaxis: GVHD

Deaths - By Cause

45 40 35 30 25 20 15 10 5 0 39 37 * Fluconazole (N=301) Posaconazole (N=299) ** 4 12 2 * 11 Adverse Event IFI - Infection Complications 2 1 31 33 Proven or Probable Infection Possible Infection Progression of Underlying Disease or GVHD Ullmann AJ et al.

New Engl J Med.

2007;356:335-47.

Comparative Efficacy in Prophylaxis

Retrospective review: 573 AML inductions over 12 years

25 20 15 10 5 0 Fluconazole Itraconazole Voriconazole Posaconazole

Ananda-Rajah et al; Hematologica 2012;97(3)

Prophylaxis:

 What are the trade-offs in the long-term ?   Cost and potential resistance Incidence within an institution (number-needed to-treat) De Pauw BE.

N Engl J Med.

2007;356:409-11.

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

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

MUHC Algorithm – Prophylaxis

FUNGAL PROPHYLAXIS AML/MDS induction Stem cell transplant GVHD AML/MDS Induction (this is the only indication for posaconazole) YES NO POSACONAZOLE 200 mg PO TID (Check for interactions, optimize absorption**)

**Absorption: Avoid acid suppressants; give with or after high fat meal or with nutritional supplement

FLUCONAZOLE Allo transplant: 400 mg PO/IV QD Autologous transplant: 200 mg IV/PO QD GVHD: 200-400 mg PO/IV QD (adjust with renal function, check for interactions)

MUHC Algorithm – Preemptive

Autologous HSCT, Consolidation, Allo HSCT pre-engraftment