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INVASIVE ASPERGILLOSIS

INVASIVE ASPERGILLOSIS. Management with liposomal amphotericin B. Michael Ellis. IPA/IFI – THE INTRINSIC SETTING. Leukemia Cancer Multiple myeloma Malnutrition. IPA/IFI – THE EXTRINSIC SETTING. Socio-behavioural HIV Longevity Super old Extreme prematurity

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INVASIVE ASPERGILLOSIS

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  1. INVASIVE ASPERGILLOSIS Management with liposomal amphotericin B Michael Ellis

  2. IPA/IFI – THE INTRINSIC SETTING • Leukemia • Cancer • Multiple myeloma • Malnutrition

  3. IPA/IFI – THE EXTRINSIC SETTING • Socio-behavioural HIV • Longevity Super old Extreme prematurity • Neonatal survivorship Congenital IDS • Antimicrobials Fungal promotion • Intravenous device Mechanical disruption • Orifice cannulation Mucosal disintegrity • SurgeryRepetitive/extensive

  4. Neutropenia risk 50 0 Duration of neutropenia Risk infection/1000 days Neutrophils <100 100-500 500-1000 1000-1500 >1500

  5. % autopsies in pts with cancer positive for IFI 80 Data from 8 studies All IFI 40 ASPERGILLUS 1950 1970 1990

  6. FEBRILE NEUTROPENIA AND IFI 92 patients with febrile neutropenia panfungal PCR q weekly 34 PCR +ve Hebart et al Br J Haematol 2000

  7. IPA in prolonged neutropenia 362 high-risk treatment episodes Laminar air flow HEPA Itraconazole/CAB +ve galactomannan 12.1% all neutropenic episodes Maertens et al Blood 2001

  8. IA IN STEM CELL RECIPIENTS % cumulative incidence 12% 4% 19901998 Marr et al Abstract #2001 ASH 2001

  9. IA in Hematological PatientsOutcome 222 studies > 1995 50 studies Case fatality rate % Lin et al CID 2001

  10. Management of IA AMBISOME 10 drug Immune-modulation surgery 20 drug

  11. CAB toxicity costs • 707 admissions/4 years to Brigham and Womens • 50% had malignancy • CAB for 33% documented IFI, 66% ARNF • Acute renal failure in 212/707 Baseline creatinine  50% Bates et al CID 2002

  12. CAB toxicity costs • MORTALITY • ARF + ARF- • 54% 16% p = 0.001 • Balanced for sepsis/infection • BMTx and total dose CAB more in ARF group • Adjusted for age, base creatinine, illness severity • Re-analysed in last two admission days Bates et al CID 2002

  13. CAB toxicity costs COST OF SURVIVING CAB associated ARF Confounders eg indications for Rx and severity of illness although corrected for may have still existed

  14. IPA CAB 0.5mg CAB 0.8mg CAB DC CAB 0.3mg Day 1 4 7 10 2cms/day in vitro

  15. Liposomal Amphotericin B • Infrequent toxic related dosing limitations • Less indication for steroids, opiates • Short infusion time • Dose escalation possible

  16. Liposomal versus conventional amphotericin B Animal data Human open trial Prospective clinical and other

  17. Liposomal versus conventional amphotericin B Intratracheal inoculation Neutropenic rabbits % lobes infected Francis et al JID 1994

  18. LIPOSOMAL VERSUS CONVENTIONAL AMPHOTERICIN B: SURVIVAL 100% Rx none CAB1 LAB1 LAB5 LAB10 Francis et al JID 1994

  19. DISSEMINATION OF ASPERGILLUS 100% Liver and spleen R lung Rx none CAB1 LAB 1 LAB 10 Rx none CAB1 LAB 1 LAB 10 Leenders JAC 1996;38:215

  20. Concentration dependency • g/ml and log cfu/g Groll et al JID 2000

  21. Liposomal versus conventional amphotericin B 13 studies involving 1091 patients Invasive aspergillosis LAB other forms 76 patients 414 patients Response 63% [59-66] Response 47% [34-67] Wong-Beringer CID 1998

  22. CAB v LAB Invasive fungal infections 106 Enrolled/analysed for efficacy 66 Invasive pulmonary aspergillosis 40 CONVENTIONAL AB AMBISOME 1 mg for 3 weeks 5 mg for 3 weeks 0.7 mg 3mg Leenders et al Br J Haematol 1998

  23. CAB v LAB: responses

  24. AmBisome optimal dosing • Animal candida thigh infection model • Neutropenic animal models • Previous human observations • In depth case studies • Histopathologic Maximum tolerated dose

  25. LIPOSOMAL VERSUS CONVENTIONAL AMPHOTERICIN B: SURVIVAL 100% Rx none CAB1 LAB1 LAB5 LAB10 Francis et al JID 1994

  26. Treatment failure in IPA and tissue drug levels MIC AB & Sensitivity Lung AB levels g/ml g/gm A.Fumigatus 0.125-0.5 S 0.22 Infected A.flavus 1 S 0.67 Normal A.flavus 2 LS 6.63 Liver Paterson et al ICAAC 2000

  27. HIGH DOSE CAB 11 PTS ARNF ON CAB 0.5 MG 4 PTS IA N = 15 0.5 MG [N = 1] 1- 1.5 MG N = 14 0/1 SURVIVAL 13/14 Burgh J Clin Oncol 1987;5:1985

  28. EORTC 19923: probable/proven IPA

  29. EORTC 19923 SURVIVAL 100% 1 MG 4 MG Log rank p = 0.58 0 1 2 3 4 5 6 months

  30. Proven IPA

  31. EORTC 19923 summary AmBisome at 1 mg or 4 mg efficacious in treating IA in neutropenic patients, appears to be superior to conventional amphotericin B and less toxic. The results suggest that the 4 mg dose has advantages over a 1 mg dose.

  32. Hepatic candidiasis CANDIDA ANTIGEN CANDIDA ANTIBODY 30 1.5 1.0 10 0.5

  33. Hepatic candidiasis LAB 5mg CASPOFUNGIN LAB 10mg LIVER image TEMP 39 38 39 39 38 37 CRP 400 110 150 190 100 30 15 DAY Rx 1 21 25 42 56 70

  34. IPA early diagnosis-AmBisome treatment link HALO SIGN The radiologic counterpart of the histopathologic early IPA lesion

  35. IPA early diagnosis-AmBisome treatment link ARNF LAB 1-3 mg 96hr HRCT for CT HALO or other [q7d] 2-4 gm 5 mg Worsens Stable 8 – 10 mg 5, 4, 3 mg NO YES

  36. IPA early diagnosis-AmBisome treatment link 21 patients Plain chest Chest radiograph CT Normal Non-specific Normal Halo signs+/- changes other changes 6 15 0 21

  37. DISTRIBUTION OF CT FINDINGS

  38. ARNF TO 1ST +VE SCAN MEDIAN

  39. IPA early diagnosis-AmBisome treatment link % 100 50 LINKED RESPONSE LITERATURE CRUDE MORTALITY ATTRIB MORTALITY 0

  40. IPA early diagnosis-AmBisome treatment link 9 DEATHS IPA 2pts non-IPA 7pts Recurrence/progression 2/2 Bacterial sepsis 3 Dosage 1.5, 3 mg Hematologic disease 3 Growth factors 1/2 Cerebral hemorrhage 1 High fungal burden 2/2

  41. CT SERIES IPA FROM DAY 16 ARNF PATIENT HAS AIR CRESCENT IN RUL, STARTS TREATMENT WITH AMBISOME DAY 16 DAY 30 DAY 120

  42. Impact of early diagnosis and Rx on survival in IPA survival 100% since 1992 before 1992 50% 0 60 120 180 days after diagnosis Caillot et al; J Clin Oncol 1992; 15: 139-147

  43. IPA early diagnosis-AmBisome treatment link CONCLUSION An early diagnosis of IPA linked to early high dose AmBisome and supportive hematologic care offers a good treatment option

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