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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. Polyenes

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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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