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

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

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) 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

Aspergillus spp. Isolates Submitted to San Antonio Fungus Testing Laboratory 918 Isolates; Jan. 2001-July 2004 AmB MFC >16 A. fumigatus 24% AmB MIC>2 A. terreus 90% A. flavus 51% A. ustus 50% A. nidulans 3% AmB=Amphotericin B; MFC=Minimum Fungicidal Concentration; MIC=Minimum Inhibitory Concentration Sutton D et al, Advances Against Aspergillus 2004 (Abstract 16)

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 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

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

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;46:3001-3012

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

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)

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% Note: OLAT=other licensed antifungal therapy Herbrecht R et al NEJM 2002;347:408-15; Patterson TF et al, Clin Infect Dis 2005;41:1448-52

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 2005 2005;41:1448-52

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 Response Categorized by Baseline CT Findings 23 23 21 26 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 b-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

for mycological criteria PCR for Invasive Aspergillosis PCR not (yet) accepted for mycological criteria Design Sens (%) Spec (%) Ref Pan-fungal 100 98 JCM 1997;35:1353-60 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;33:1504-12 64 BJH 2004;125:196-202 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

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 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%) 21/422 (5%) 8/415 (1.9%) Walsh TJ et al, New Engl J Med 2002;346:225-34 1 19 1

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;351:1391-1402

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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