1. Treatment of Invasive Aspergillosis: Polyenes, Azoles, Echinocandins
Treatment of Invasive Aspergillosis: Polyenes, Azoles, Echinocandins? Thomas F. Patterson, MD Professor of Medicine Director, San Antonio Center for Medical Mycology The University of Texas Health Science Center at San Antonio

2. New (and newer) antifungals for invasive aspergillosis
Polyenes
ABLC, ABCD,
AmBisome
liposomal nystatin
inhaled amphotericin B
Azoles
itraconazole (i.v.)
voriconazole
posaconazole
ravuconazole
BAL 8557/4815
Echinocandins
caspofungin
micafungin
anidulafungin
aminocandin
Note: Blue text, earlier stage development
Note: ABLC=amphotericin B lipid complex; ABCD= amphotericin B colloidal dispersion

3. Treatment of Invasive Aspergillosis: Polyenes, Azoles, or Echinocandins?
Key questions:
Why have outcomes been so bad?
What is the impact of early diagnosis?
What are options for therapy?
Disseminated infection?
Severely immunocompromised?
Can we do better?
Role of combination therapy?
How can management strategies improve outcome?

4. Invasive Aspergillosis in Transplant Recipients
Type of Transplant
Incidence Range, % (Mean)
Mortality (%)
Lung
3-14% (6%)
68%
Liver
1-8 (2) 87
Heart
1-15 (5) 78
Kidney
0-4 (1) 77
Small bowel
0-10 (2) 66
Allogeneic stem cell
5-26 (10)
78-92
Autologous stem cell
2-6 (5)
Nonmyeloblative stem cell
8-23 (11)
63-67
Singh N & Paterson DL, Clin Microbiol Rev 2005;18:44-69.

5. Acute Renal Failure and Amphotericin B: Hidden Costs of Toxicity
Mortality and costs of acute renal failure
707 adult patients receiving amphotericin B
Clinical impact
Acute renal failure: 212 (30%)
Higher mortality with acute renal failure: 54% vs 16%
Economic impact
Mean increase length of hospital stay: 8.2 days
Mean increase hospital cost: $29,823
Bates DW et al, Clin Infect Dis, 2001;32:686-93

6. Aspergillus spp. Isolates Submitted to San Antonio Fungus Testing Laboratory
918 Isolates; Jan July 2004
AmB MFC >16
A. fumigatus 24%
AmB MIC>2
A. terreus %
A. flavus %
A. ustus %
A. nidulans 3%
AmB=Amphotericin B; MFC=Minimum Fungicidal Concentration;
MIC=Minimum Inhibitory Concentration
Sutton D et al, Advances Against Aspergillus 2004 (Abstract 16)

7. Lipid Preparations of Amphotericin B: Rationale for Use
Polyene: broad spectrum of activity
Lipid formulations of amphotericin B
Reduced toxicities of intravenous amphotericin B deoxycholate
Improved therapeutic index: ≥5 mg/kg/d well tolerated
Salvage therapy (limited efficacy 40% responded)
Empiric therapy (reduced efficacy vs moulds at lower doses)
Limited data for primary therapy; most studies in empirical use
Target use for patients with documented need (eg Zygomycosis, intolerance or progressive infection)
Cost remains significant obstacle to use!

8. Efficacy of Liposomal AmB (L-AmB) in Invasive Mycoses: AmBiLoad Trial
14 day loading dose of L-AmB 3 or 10 mg/kg/d followed by L-AmB 3 mg/kg/d
L-AmB 3
L-AmB 10
IPA
96%
97%
CT Halo 58 60
Allo-SCT 16 19
Neutropenia 71 76
Survival 72 59
Toxicity 20 32
Note: L-AmB=liposomal amphotericin B; CR+PR=complete & partial responses; EOT=End of Therapy; IPA=invasive pulmonary aspergillosis;
Allo-SCT=allogeneic stem cell transplant
Cornely O et al. ASH 2005 (Abstract 3222) 34 27

9. Continuous Infusion Amphotericin B
24 hour continuous infusion
Dose escalated to 2 mg/kg/d when tolerated
Median duration of therapy 16 d (range 7-72d)
Infusion-related reactions: 18%
>2-fold increase in creatinine: 16%
Dose-limited toxicity: 1/33
Concerns
Limited efficacy data in documented infection
Poor efficacy of amphotericin B in invasive aspergillosis
Animal models: Peak serum level/MIC best predictor of outcome
Imhof A, et al, Clin Infect Dis 2003:36:943-51;
Andes D, et al, Antimicrob Agents Chemother 2001;45:922-6

10. In Vitro Effects of Echinocandins on Growth of Aspergillus
Living Cells
Dead
Cells
Control Cells
AmB
Caspo
Itra
Amphotericin B 0.15 g/mL
Caspofungin 0.30 g/mL
Itraconazole 2.6 g/mL
In vitro activity:
Not classically fungicidal or fungistatic
Activity against other Aspergillus spp. (A terreus)
Animal models prolonged survival
Bowman et al. Antimicrobial Agents Chemother 2002;46:

11. Echinocandins in Invasive Aspergillosis%
Study conducted in patients with well-documented, refractory infection
Efficacy
Progressive infection
Multiple prior antifungals
Excellent tolerability
Clinical utility for moulds
Combination therapy (not primary therapy)
Activity: Aspergillus (not Zygomycetes or other moulds)
Maertens J et al. Clin Infect Dis 2004;39:

12. Posaconazole Salvage Therapy for Invasive Aspergillosis
Open, salvage therapy; historical controls refractory or intolerant of standard therapy
Posaconazole: Oral solution (200mg qid X2 wk/400mg bid)
Adverse events: 4-10% (Headache, abdominal pain, nausea, liver enzyme elevations)
Aspergillus species
Posaconazole (n)
Historical Controls (n)
All Aspergillus
42% (107)
26% (86)
A. fumigatus
41% (29)
35% (34)
A. flavus
53% (19)
19% (16)
A. terreus
29% (14)
18% (11)
Raad I, et al. ICAAC 2004 (Abstract M-669)

13. Voriconazole in Invasive Aspergillosis: Global Comparative Study%
Satisfactory (Complete/Partial Responses) at week 12
Difference: %
Improved survival with voriconazole
Importance of early therapy
Limited role for rescue therapy
Lower success in high risk patients
Disseminated infection
Allogeneic Bone Marrow Transplantation
Voriconazole: %
Amphotericin B: 13.3%
Note: OLAT=other licensed antifungal therapy
Herbrecht R et al NEJM 2002;347:408-15;
Patterson TF et al, Clin Infect Dis 2005;41:

14. The Strategy of Following Voriconazole (Vori) or Amphotericin B (AmB) with Other Licensed Antifungal Therapy (OLAT)
Category/Reason for switch
Success at wk 12 (%)
Vori (n=144)
AmB (n=133)
Received OLAT
25/52 (48%)
41/107 (38%)
Intolerance (adverse event, lab abnormality)
8/19 (42)
27/74 (36)
Insufficient clinical response
5/16 (31)
4/19 (21)
Completed therapy and received OLAT
11/14 (79)
6/10 (60)
Other
1/3
4/4
Overall success
76/144 (53)
42/133 (32)
Pts switched to lipid formulations of AmB following initial AmB had success in 14/47 (30%)
No antagonism demonstrated with AmB following Voriconazole
Herbrecht R et al. NEJM 2002;347:408-15;
Patterson TF et al. Clin Infect Dis ;41:

15. Voriconazole: Important Considerations
Watch for drug interactions
Significant adverse events: hepatic, visual, rash
IV formulation: accumulation of cyclodextrin in renal insufficiency
Potential for azole cross-resistance
No activity versus Zygomycetes

16. Patients with Satisfactory Treatment Response Categorized by Baseline CT Findings23 23 21 26
Herbrecht R et al NEJM 2002;347:408-15;
Patterson TF et al, Clin Infect Dis 2005;41: ;
Greene R et al. ECCMID 2003

17. Non-Culture Based Diagnosis of Invasive Aspergillosis
Galactomannan
Sandwich ELISA (Platelia)
PCR
TaqMan, LightCycler PCR
18s ribosomal DNA
Multi-copy or single target genes
b-D-glucan
Amebocyte Limulus lysate
Chromogenic (Fungitell)
Kinetic (Wako)

18. Screening for Invasive Aspergillosis using Aspergillus Platelia EIA
Maertens et al (2001)
Sensitivity: 89%; Specificity: 98%
Serial testing needed for optimal results
Herbrecht et al (2002); Marr et al (2004)
Limited sensitivity (43-70%); Better specificity (70-93%)
Lower cut-off on empirical antifungals or prophylaxis
Original criteria: Pos (Index ) on 2 consecutive samples
US: Pos (0.5) on repeat testing (same sample)
EU: Pos ( ); dynamic endpoint (Maertens, 2005)
False-positive results (Verweij, 1998)
Weakly positive samples ■ Cross-reactivity
Laboratory contamination ■ Dietary
Piperazillin/Tazobactam (Viscoli, 2003; Sulahian, 2003)

19. Detection of GM in the Diagnosis & Management of Invasive Aspergillosis
Utility of GM at baseline
Patients with EORTC/MSG confirmed IA
60/144 (41.7%) positive (O.D. ≥ 0.5)
Limited number of samples
Utility of GM in serial samples
Poor correlation between baseline level & response
Trend to poorer clinical response with higher antigen titers after 5 days
Herbrecht R et al, Advances Against Aspergillosis, 2004

20. Utility of -Glucan Detection in Invasive Fungal Infection
30 candidemic pts/30 controls
Cut-off >60 pg/ml
283 pts AML/MDS (twice weekly samples)
Sensitivity: 20/20 IFI pts at least one positive
Specificity: 90%
Organisms detected: Candida, Aspergillus, Trichosporon, Fusarium
163 pt IFI/170 controls (single samples)
Sensitivity: 70%
Specificity: 87%
Obadasi Z et al. Clin Infect Dis 2004;39: ;
Ostrosky-Zeichner L et al. Clin Infect Dis 2005;41:654-9

21. for mycological criteria
PCR for Invasive Aspergillosis
PCR not (yet) accepted
for mycological criteria
Design
Sens (%)
Spec (%)
Ref
Pan-fungal
100 98
JCM 1997;35: 75 96
BJH 2001;113:180-4
Asp. sp. 65
JID 2000;181:1713-9
91.7
81.3
CID 2001;33:428-35 79 92
CID 2001;33: 64
BJH 2004;125: 95
CID 2006;42:479-82
Variable sensitivity / specificity
Limited per test positivity
Technical false positives/negatives
Lack of standardized targets/reagents
Not externally validated
Donnelly JP. Clin Infect Dis 2006;42:487-9

22. Diagnostic Strategies in Invasive Aspergillosis
Consideration of risk
Role of mycological diagnosis
Predictive value of positive cultures in high risk patients
Utility of radiological procedures
Non-culture based diagnostics
Impact of antifungal therapies
Value of serial samples
Significance of false negative/false positive results
Role of testing in other body fluids, including CSF & BAL
Role of surrogate markers in decision making & impact on mortality

23. Combination Therapy: Candins
In vitro
Most interactions show synergy / additive effects (Perea, 2002)
Poor correlation between in vitro results and in vitro efficacy (Johnson, 2004)
Experimental infections
Candin plus polyene (Kohno, 2000; Nakajima, 2000)
Candin plus azole (Kirkpatrick, 2002; Petraitiene, 2002)
Improved sterilization of tissues
Reduced tissue burden
Anecdotal clinical series
Candin+polyene (Aliff, 2003; Kontoyiannis, 2003; Ratanatharathorn, 2002)
Candid plus azole (Marr, 2004)

24. Efficacy of Empirical Antifungal Therapy in Neutropenic Patients
Voriconazole vs liposomal amphotericin B
Composite success: % vs 31%
High risk patients: 18% allogeneic BMT
Similar survival, fever resolution, toxicity or lack of efficacy
Fewer breakthrough infections
Efficacy in high risk:
Breakthrough infections: 2/143 (2%) vs 13/143 (9%)
21/422
(5%)
8/415
(1.9%)
Walsh TJ et al, New Engl J Med 2002;346:225-34 1 19 1

25. Caspofungin vs Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Fever & Neutropenia
Caspofungin
(n=556)
Liposomal Amphotericin B
(n=539)
Composite Success
33.9%
33.7%
Success Baseline Infections
14/27 (52%)
7/27 (26%)
Breakthrough Infections
29 (5.2%)
24 (4.5%)
Etiological Agents*
Aspergillus 10 9
Candida 16 15
Fusarium 1
Zygomycetes 2
Other
*Patients may have had more than one organism
Walsh TJ et al, New Eng J Med, 2004;351:

26. Invasive Aspergillosis: Polyenes, Azoles or Echinocandins?
Importance of early detection
Role of radiological diagnosis
Non-culture based diagnostics
Importance of serial samples
Impact of prior therapy
Poorer outcomes with extensive disease
Poor efficacy of amphotericin B in high risk patients
Improved responses with early effective therapy
Utility of early targeted therapy
Role of new agents in invasive aspergillosis
Efficacy of voriconazole as primary therapy
Options for salvage therapy: posaconazole, echinocandins, lipid amphotericin formulations
Clinical trials needed combination therapy

27. Thank you!
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