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New (and newer) antifungals for invasive aspergillosis

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.

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New (and newer) antifungals for invasive aspergillosis

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  1. Treatment of Invasive Aspergillosis:Polyenes, Azoles, Echinocandins?Thomas F. Patterson, MDProfessor of MedicineDirector, San Antonio Center for Medical MycologyThe University of Texas Health Science Centerat 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 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. 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)

  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 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)

  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. AmB Caspo Itra Amphotericin B0.15 g/mL Caspofungin0.30 g/mL Itraconazole2.6 g/mL ControlCells LivingCells Dead Cells 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 Bowman et al. Antimicrobial Agents Chemother 2002;46:3001-3012

  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;39:1563-71

  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) 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: 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

  14. 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

  15. 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 Voriconazole: Important Considerations

  16. Patients with Satisfactory Treatment ResponseCategorized 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

  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 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)

  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;39:199-205; Ostrosky-Zeichner L et al. Clin Infect Dis 2005;41:654-9

  21. PCR for Invasive Aspergillosis PCR not (yet) accepted for mycological criteria • 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. 21/422 (5%) 8/415 (1.9%) 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%) Walsh TJ et al, New Engl J Med 2002;346:225-34

  25. Caspofungin vs Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Fever & Neutropenia *Patients may have had more than one organism Walsh TJ et al, New Eng J Med, 2004;351:1391-1402

  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! Want to know more?www.doctorfungus.org

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