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My Home Town a Few Days Ago. Relevance of Combination Antifungal Therapy: Some Key Questions Is there a need for combination therapy in the first place?

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Presentation on theme: "My Home Town a Few Days Ago. Relevance of Combination Antifungal Therapy: Some Key Questions Is there a need for combination therapy in the first place?"— Presentation transcript:

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 Practical Advantages of Antifungal Combination Therapy From Kontoyiannis and Lewis Synergy Broader Spectrum Decreased Resistance Pharmacokinetic Enhancement Better Tolerance with Lower Doses

4 Combination Strategies Unique to Fungal Infections Overall Mortality Rates Very High Toxicity of Antifungals is Significant Fungal Diseases Relatively Rare Drug Costs High Superiority Trials for Efficacy Preferred Costs of Studies Enormous Considerations in Clinical Trials of Combination Antifungal Therapy: John H. Powers CID 39: S228: 2004

5 Surrogate Endpoints Rare/non-existent Multiple Companies Needed for Studies Historical Trials Problematic Relatively Few Agency Approved Drugs Standard of Care May Be Combinations Unique Aspects of Combination Treatment for Fungal Infections 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 Voriconazole Interactions Warfarin Cyclosporin Tacrolimus Sulfonureas Statins Benzodiazepines Vinca Alkaloids Sirolimus Rifabutin Rifampicin Terfenadine

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

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

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

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

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

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

17 Combination Therapy for Invasive Aspergillosis: Marr et al. : CID 39:737, 2004

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

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

20 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) All Cause Mortality Caspo + OLAT N=31 P=0.1 N=63 *More immunostim

21 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

22 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) Probability of Attributable Death in Patients Receiving and not Receiving Voriconazole Other Voriconaozle Probability of Death Due to IA No. of Days After IA Diagnosis P=.03 N=54 N=176

23 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

24 Selected Combination Studies for Aspergillosis

25 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 All Patients n=3060% Response Chemotherapy for Acute Leukemia n=20 75% Response Survival at Discharge Higher with Patients Having a Favorable Response

26 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)

27 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%

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

29 Combination Salvage Therapy of Invasive Aspergillosis in Patients with Hematologic Malignancy: Which Caspofungin-Containing Regimen? Raad et al. 47 th ICAAC Abstract M-624, 2007 (Salvage Study) 595248%85% 335812%64% Number of Patients Patient age Acute Leukemia GCSF Or Other Caspo +LPAMB Caspo + Vor All Statistically Significant

30 In Vitro Synergy Testing of Rifampicin with Caspofungin and Amphotericin B against Aspergillus spp. And Fusarium spp.: Odabasi et al.: 47 th ICAAC, Abstract M-546, 2007 Conclusions: Combination of Rifampicin with Amphotericin B seems very active against commonly seen molds: Adding Rifampicin to Caspofungin may show some additive effects: Amphotericin B and Rifampicin combinations should be further tested with in-vivo studies

31 Single Agent or Combination to Treat Invasive Aspergillosis? Kubin et al. 46 th ICAAC, Abstract M-899, 2006 Response 24%21% 12 Week Mortality 55%46% Mono N=124 47 AMB: 33 Vori Caspo + Vori N=22 Retrospective 146 proven/probable primary cases

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

33 Antifungal Interactions with the Triple Combination of Amphotericin B, Caspofungin, and Voriconazole Against Aspergillus Species OShaughnessy et al. J ANtimicrob Chemother 58:1168, 2006 Syngergism at Low Concentrations AMB.1-.22 mg/L Vori.07-.15 mg/L Caspo 1.47-32 mg/L Antagonism at High Concentrations AMB.3-.5 mg/L Vori.23-.68 mg/L Caspo Same Range

34 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) Percent Survival PrimarySalvage 225 Patients 6/12 5/17 9/22 60/174 98/225 HSCT: 88/98 /allo 48 GVHD 83/225 Received Chemo For Malignancy

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

36 Combination Strategies for Non-Aspergillus Fungi

37 Fluconazole Plus Amphotericin B vs AMB Alone for Primary Treatment of AIDS-Associated Cryptococcal Meningitis; Results of a Phase II Trial Pappas et al. 47 th 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

38 Fluconazole Plus Amphotericin B vs AMB Alone for Primary Treatment of AIDS-Associated Cryptococcal Meningitis; Results of a Phase II Trial Pappas et al. 47 th ICAAC Abstract M-626, 2007 N=46 % Success: 41 N=42 % Success: 31 N=42 % Success: 55 N=37 % Success: 76 N=35 % Success: 80 N=33 % Success: 85 N=38 % Success:76 N=32 % Success:88 N=28 % Success:93 Standard Rx Low Dose High Dose Day 14 Day 42 Day 70

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

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

41 Combination Polyene-Echinocandin Therapy in the Treatment of Mucormycosis Reed et al. 45 th 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

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

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

44 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.

45 Grazie!


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