treatment of invasive aspergillosis: polyenes, azoles, echinocandins? thomas f. patterson, md...
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Treatment of Invasive Aspergillosis:
Polyenes, Azoles, Echinocandins?
Thomas F. Patterson, MDProfessor of Medicine
Director, San Antonio Center for Medical Mycology
The University of Texas Health Science Centerat San Antonio
New (and newer) antifungals for invasive aspergillosis
Azoles
• itraconazole (i.v.)
• voriconazole
• posaconazole
• ravuconazole
• BAL 8557/4815
Echinocandins
• caspofungin
• micafungin
• anidulafungin
• aminocandin
Polyenes
• ABLC, ABCD,
AmBisome
• liposomal nystatin
• inhaled amphotericin B
Note: ABLC=amphotericin B lipid complex; ABCD= amphotericin B colloidal dispersion
Note: Blue text, earlier stage development
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?
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) 78-92
Nonmyeloblative stem cell 8-23 (11) 63-67
Singh N & Paterson DL, Clin Microbiol Rev 2005;18:44-69.
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
A. flavus12%
A. niger10%
A. sydowii2%
A. ustus2%
A. versicolor2%
A. fumigatus57%
A. terreus12%
Aspergillus spp. Isolates Submitted to San Antonio Fungus Testing Laboratory918 Isolates; Jan. 2001-July 2004
AmB=Amphotericin B; MFC=Minimum Fungicidal Concentration; MIC=Minimum Inhibitory ConcentrationSutton D et al, Advances Against Aspergillus 2004 (Abstract 16)
A. nidulans 3%
AmB MFC >16 A. fumigatus 24%
AmB MIC>2 A. terreus 90% A. flavus 51% A. ustus
50%
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!
Efficacy of Liposomal AmB (L-AmB) in Invasive Mycoses: AmBiLoad Trial
Proven/Probable Invasive Fungal Infection
50% 46%
0
20
40
60
80
100
L-AmB 3 mg/kg/d(n=107)
L-AmB 10 mg/kg/d(n=94)
Resp
onse
at E
OT (C
R+PR
) (%
)
• 14 day loading dose of L-AmB 3 or 10 mg/kg/d followed by L-AmB 3 mg/kg/d
Cornely O et al. ASH 2005 (Abstract 3222)
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
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
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
Bowman et al. Antimicrobial Agents Chemother 2002;46:3001-3012
In Vitro Effects of Echinocandins on Growth of Aspergillus
In vitro activity: • Not classically
fungicidal or fungistatic
• Activity against other Aspergillus spp. (A terreus)
• Animal models prolonged survival
LivingCells
DeadCells
ControlCells
AmBAmB CaspoCaspo ItraItraAmphotericin B
0.15 g/mLCaspofungin0.30 g/mL
Itraconazole2.6 g/mL
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;39:1563-71
Proven/Probable Invasive Aspergillosis
41
17
0
20
40
60
80
100
Caspofungin(n=56)
HistoricalControls (n=206)
Com
plet
e/Pa
rtial
Res
pons
es(%
)
%
%
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)
Raad I, et al. ICAAC 2004 (Abstract M-669)
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)
Voriconazole in Invasive Aspergillosis: Global Comparative Study
• Satisfactory (Complete/Partial Responses) at week 12 Difference: 21.2%
• 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: 32.4%- Amphotericin B: 13.3%
Responses at week 12
31.6
52.8
0
20
40
60
80
100
Voriconazole ±OLAT (n=144)
Amphotericin B ±OLAT (n=133)
Com
plet
e/Par
tial R
espo
nses
(%)
%
%
Herbrecht R et al NEJM 2002;347:408-15;Patterson TF et al, Clin Infect Dis 2005;41:1448-52
Note: OLAT=other licensed antifungal therapy
The Strategy of Following Voriconazole (Vori) or Amphotericin B (AmB) with Other Licensed
Antifungal Therapy (OLAT)
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 2005 2005;41:1448-52
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)
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
Patients with Satisfactory Treatment ResponseCategorized by Baseline CT Findings
60%
53%
45%
67%
37%32%
19%
44%
0%
10%
20%
30%
40%
50%
60%
70%
ALL Patients Definite Probable Probable(Radiology alone)
Sati
sfa
cto
ry (
Co
mp
lete
/Part
ial)
Resp
on
ses
Voriconazole
Amphotericin B
2126
2323
Herbrecht R et al NEJM 2002;347:408-15;Patterson TF et al, Clin Infect Dis 2005;41:1448-52;Greene R et al. ECCMID 2003
Non-Culture Based Diagnosis of Invasive Aspergillosis
• Galactomannan Sandwich ELISA (Platelia)
• PCR TaqMan, LightCycler PCR 18s ribosomal DNA Multi-copy or single target genes
• -D-glucan Amebocyte Limulus lysate Chromogenic (Fungitell) Kinetic (Wako)
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 1.0-1.5) on 2 consecutive samples- US: Pos (0.5) on repeat testing (same sample)- EU: Pos (0.5-0.7); dynamic endpoint (Maertens, 2005)
• False-positive results (Verweij, 1998) Weakly positive samples ■ Cross-reactivity Laboratory contamination ■ Dietary Piperazillin/Tazobactam (Viscoli, 2003; Sulahian, 2003)
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
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;39:199-205; Ostrosky-Zeichner L et al. Clin Infect Dis 2005;41:654-9
Design Sens (%) Spec (%) Ref
Pan-fungal 100 98 JCM 1997;35:1353-60
Pan-fungal 75 96 BJH 2001;113:180-4
Asp. sp. 100 65 JID 2000;181:1713-9
Asp. sp. 91.7 81.3 CID 2001;33:428-35
Asp. sp. 79 92 CID 2001;33:1504-12
Asp. sp. 64 64 BJH 2004;125:196-202
Asp. sp. 92 95 CID 2006;42:479-82
PCR for Invasive Aspergillosis
•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
PCR not (yet) accepted for mycological criteria
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
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)
Efficacy of Empirical Antifungal Therapy in Neutropenic Patients
Walsh TJ et al, New Engl J Med 2002;346:225-34
4
13
4
8
0 5 10 15 20 25
Vori(n=415)
L-AmB(n=422)
Fungal Infections (#)
Aspergillus Other
21/422 (5%)
8/415 (1.9%)
• Voriconazole vs liposomal amphotericin B
Composite success: 26% 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%)
Caspofungin vs Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients
with Fever & Neutropenia
Walsh TJ et al, New Eng J Med, 2004;351:1391-1402*Patients may have had more than one organism
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 0
Zygomycetes 2 0
Other 1 1
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
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