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  1. My Home Town a Few Days Ago

  2. Relevance of Combination Antifungal Therapy: Some Key Questions Is there a need for combination therapy in the first place? Does the toxicity risk merit the use in attaining a “possible” mortality reduction?” Are the doses of the investigational drugs appropriate? Is the endpoint of the study meaningful?

  3. SynergyBroader SpectrumDecreased ResistancePharmacokinetic EnhancementBetter Tolerance with Lower Doses Practical Advantages of Antifungal Combination Therapy From Kontoyiannis and Lewis

  4. Overall Mortality Rates Very HighToxicity of Antifungals is SignificantFungal Diseases Relatively RareDrug Costs HighSuperiority Trials for Efficacy PreferredCosts of Studies Enormous Combination Strategies Unique to Fungal Infections Considerations in Clinical Trials of Combination Antifungal Therapy: John H. Powers CID 39: S228: 2004

  5. Unique Aspects of Combination Treatment for Fungal Infections Surrogate Endpoints Rare/non-existentMultiple Companies Needed for StudiesHistorical Trials ProblematicRelatively Few Agency Approved DrugsStandard of Care May Be Combinations Considerations in Clinical Trials of Combination Antifungal Therapy: John H. Powers CID 39: S228: 2004

  6. Relevance of Combination Antifungal Therapy: Some Key Questions Is there a need for combination therapy in the first place? Definite: Aspergillosis Mucormycosis Fusarium, Scedoporium, and other moulds Coccidiomycosis Probable Cryptococcosis Candidiasis: Especially specific forms such as endocarditis, osteomyelitis, and endophthalmitis

  7. Successfully Treated Candida krusei Infection of the Lumbar Spine with Combined Caspofungin/posaconazole Therapy: Schilling et al. Medical Mycology Jan 2007

  8. Relevance of Combination Antifungal Therapy: Some Key Questions Does the toxicity risk merit the use in attaining a “possible” mortality reduction?”

  9. WarfarinCyclosporinTacrolimusSulfonureasStatinsBenzodiazepinesWarfarinCyclosporinTacrolimusSulfonureasStatinsBenzodiazepines Vinca AlkaloidsSirolimusRifabutinRifampicinTerfenadine Voriconazole Interactions

  10. Relevance of Combination Antifungal Therapy: Some Key Questions Are the doses of the investigational drugs appropriate?

  11. Success % Synergism vs Cryptococcal Meningitis N Engl J Med: 301:126, 1979 51 Courses, 10wks AMB Alone vs. 6 Weeks of Combo 67% Combo 5-FC: 150mg/kg/d + Amb: 0.3 mg/kg/d AMB: 0.4 mg/kg/d 41%

  12. Relevance of Combination Antifungal Therapy: Some Key Questions Is the endpoint of the study meaningful? Time of the End Point Analysis Surrogate Marker End Point Cost of Care Use of Alternative Strategies Toxicity Retrospective Subgroup Analysis Underlying Condition of Patient All Cause Mortality Fungal Related Mortality Break Through Fungal Infection Composite Endpoint Microbiologic Cure Clinical Cure

  13. Relationship Between Severity of Disease at Baseline, As Measured by APACHE II, and Clinical Outcomes: From Rex et al. Clin Inf Dis: 36:1221, 2003

  14. Vori + Caspo Combination N=40 P=0.1 P Probability of Survival N=47 Lipid Ampho Group Days Post Diagnosis Combination of Voriconazole and Caspofungin as Primary Therapy for Invasive Aspergillosis in Solid Organ Transplant Recipients: A Prospective, Multicenter, Observational StudySingh et al. Transplantation 81:320, 2006 Vori + Caspo Mortality Due to IA: 26% LAMB Grp Mortality Due to IA: 43%

  15. Singh et al. to Bal Regarding Mortality Stratified by DiseaseTransplantation, Letter p291, 2006 Conclusion: Condition of the Patients did not Influence Outcome

  16. Vori + Caspo n=16 P=.048 n=31 Combination Therapy for Invasive Aspergillosis: Marr et al. : CID 39:737, 2004 (Retrospective, Salvage)

  17. Days After Diagnosis Vori + Caspo Probability of Survival % P=0.26 Voriconazole Survival After Combination Therapy for Aspergillosis: Marr et al. Clin Inf Dis 40:1074, 2005 The benefit of the combination treatment seen at 90 days was not present when the survival at a year was analyzed.

  18. Vori + Caspo Combo Probability of Survival Probability of Survival Combo Vori Vori Vori * Death Due To IA Death Due To IA Combo Combo Combo Death From Other Death From Other Combo * Vori Marr in Response to Cesaro and Visintin: CID 40:1075, 2005 One year data related to causes of death

  19. Caspo + OLAT *More immunostim P=0.1 N=31 N=63 All Cause Mortality High-dose Caspofungin (100mg/d) Combination Antifungal Therapy in Patients with Hematologic Malignancies and Hematopoietic Stem Cell Transplantation: Safdar et al. Bone Marrow Trans: 39:157:2007 (Retrospective)

  20. Invasive Aspergillosis Following Hematopoietic Cell Transplantation: Outcomes and Prognostic Factors Associated with Mortality: Upton et al. CID 44:531: 2007 (Retrospective, 405 Patients) Probability of Attributable Death in Patients With IA according to Years Year of Diagnosis

  21. Probability of Attributable Death in Patients Receiving and not Receiving Voriconazole Other Probability of Death Due to IA Voriconaozle N=176 P=.03 N=54 No. of Days After IA Diagnosis Invasive Aspergillosis Following Hematopoietic Cell Transplantation: Outcomes and Prognostic Factors Associated with Mortality: Upton et al. CID 44:531: 2007 (Retrospecive Analysis of 405 Patients)

  22. Invasive Aspergillosis Following Hematopoietic Cell Transplantation: Outcomes and Prognostic Factors Associated with Mortality: Upton et al. CID 44:531: 2007 (Retrospective Analysis of 405 Patients) Reasons for Improved Survival Over Time: Change in Transplant Practices Non-myeloablative Suppression Stem Cell Transplantation Improved Diagnosis of Aspergillosis Use of Voriconazole Interpreting Historical Controls May Be Highly Complex

  23. Selected Combination Studies for Aspergillosis

  24. Refractory Fungal Pneumonia in Patients with Acute Leukemia: Successful Treatment with Combination Caspofungin and Amphotericin B: Aliff et al. Cancer 97:1025, 2003 (Retrospective, Salvage Study) Proven, Probable, and Possible (Most Possible) 30 Patients Total: Retrospective Study Response=Improvement Survival at Discharge Higher with Patients Having a Favorable Response

  25. Multicenter, Noncomparative Study of Caspofungin in Combination With Other Antifungals as Salvage Therapy in Adults With Invasive Aspergillosis. Maertens et al. Cancer 107:2888, 2006 (Open Label, Non-Comparative, Refractory or Intolerant)

  26. High Dose Ambisome vs. Ambisome + Caspo For Aspergillosis: Caillot et al. Cancer, Oct. 16, 2007 15 Patients Each Arm: High Dose AMB 10mg/kg, Standard 3mg/kg Survival at Week 12: High Dose Ambisome 80% Combo 100%

  27. * * LP-AMB + Caspo Percent Vori + Caspo *: Sig Response Rate All Cause Mortality IA Mortality Renal Toxicity Res Combination Salvage Therapy of Invasive Aspergillosis in Patients with Hematologic Malignancy: Which Caspofungin-Containing Regimen? Raad et al. 47th ICAAC Abstract M-624, 2007 (Retrospective, Salvage Study) 59 33

  28. Combination Salvage Therapy of Invasive Aspergillosis in Patients with Hematologic Malignancy: Which Caspofungin-Containing Regimen? Raad et al. 47th ICAAC Abstract M-624, 2007 (Salvage Study) GCSF Or Other Number of Patients Patient age Acute Leukemia Caspo +LPAMB Caspo + Vor All Statistically Significant

  29. Single Agent or Combination to Treat Invasive Aspergillosis? Kubin et al. 46th ICAAC, Abstract M-899, 2006 Retrospective 146 proven/probable primary cases Mono N=124 47 AMB: 33 Vori Caspo + Vori N=22

  30. Retrospective, 238 Proven/Probable Cases with Hematological Malignancy 1999-2003 Posa + Caspo N=43 LAMB + Caspo N=48 29% Response 14% 24% 32% Excluding ICU Caspofungin Plus Posaconazole vs. Liposomal Amphotericin B for Aspergillosis: Raad et al. 45th ICAAC, Abstract M-1035, 2004 Survival at Discharge Higher with Posa Combination Therapy

  31. 225 Patients Primary Salvage 6/12 9/22 Percent Survival 60/174 5/17 Micafungin, Alone or in Combination with Other Systemic Antifungal Agents, for the Treatment of Acute Invasive Aspergillosis: Denning et al. J of Infect, 53:337, 2006 (Open Label, Non-Comparative, Prospective) 98/225 HSCT: 88/98 /allo 48 GVHD 83/225 Received Chemo For Malignancy

  32. Micafungin, Alone or in Combination Against Aspergillus Kontoyiannis et al. 46th ICAAC, Abstract M-878, 2006 Refractory in Bone Marrow Transplant Patients N=8 N=90 Response % 38% 24 %

  33. Combination Strategies for Non-Aspergillus Fungi

  34. Fluconazole Plus Amphotericin B vs AMB Alone for Primary Treatment of AIDS-Associated Cryptococcal Meningitis; Results of a Phase II Trial Pappas et al. 47th ICAAC Abstract M-626, 2007 Standard Therapy: 0.7 mg/kg AMB for 14 days then 8 weks of 400 mg Flu Low Dose: AMB plus 400mg of Flu for 14 days then 400 mg Flu for 8weeks High Dose: AMB plus 800mg of Flu for 14 days ten 800 mg Flu for 8 weeks Success for End Point: CSF Cultures neg, neurological stability, and survival at day 14

  35. Day 14 Day 42 Day 70 Fluconazole Plus Amphotericin B vs AMB Alone for Primary Treatment of AIDS-Associated Cryptococcal Meningitis; Results of a Phase II Trial Pappas et al. 47th ICAAC Abstract M-626, 2007 Standard Rx High Dose Low Dose

  36. Activity of Caspofungin Alone and in Combination with Amphotericin B Lipid Complex in a Murine Model of Fusariosis: Ostrosky-Zeichner et al. 47th ICAAC Abstract M-1841, 2007 25 Mice Per Group * Percent Survival Placebo Caspo 10mg/kg ABLC 10mg/kg Combo 10mg Combo 5mg

  37. Survival % Synergism of L-AMB and Micafungin Combination in Murine Mucormycosis: Spellberg et at. 46th ICAAC, Abstract M-1744, 2006

  38. Combination Polyene-Echinocandin Therapy in the Treatment of Mucormycosis Reed et al. 45th IDSA, Abstract 659, 2007 10 Year Retrospective Review Endpoint: Survival for 30 Days Following Discharge 10 Patients Found: All rhinocerebral (9/10) CNS Involvement Combination echinocandin + Polyene: 3/3 survivors Polyene alone: 1/7 Survivors Conclusion: Prospective Investigation of combination Polyene- Echinocandin Therapy for the Treatment of Mucormycosis is Warranted

  39. Deferasirox Placebo Desferoxamine The Iron Chelator Deferasirox Protects Mice From Mucormycosis Through Iron Starvation: Ibrahim et al. JCI 117:2649: 2007

  40. The Iron Chelator Deferasirox Protects Mice From Mucormycosis Through Iron Starvation: Ibrahim et al. JCI 117:2649: 2007 Deferasirox Chelator Combined with L-AMB Placebo Desferoxamine

  41. Summary: Relevance of Combination Therapy Majority of existing studies are anecdotal, retrospective, and or non-comparative Prospective, double blind studies are exceedingly problematic in design issues and feasibility Prospective, double blind, trials will be forthcoming but highly restricted in number Weight of the evidence is in favor of combination therapy in seriously ill patients with invasive fungal infections Until studies are completed, use combination therapy in serious cases Tolerance of the patient for the combination needs to be carefully monitored to justify the use.

  42. Grazie!