Treatment of Invasive Aspergillosis: Polyenes, Azoles, Echinocandins? Thomas F. Patterson, MD Professor of Medicine Director, San Antonio Center for Medical.

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

Thank you!

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