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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 l.jpg

INVASIVE ASPERGILLOSIS

Management with liposomal amphotericin B

Michael Ellis


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IPA/IFI – THE INTRINSIC SETTING

  • Leukemia

  • Cancer

  • Multiple myeloma

  • Malnutrition


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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


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Neutropenia risk

50

0

Duration of neutropenia

Risk infection/1000 days

Neutrophils <100 100-500 500-1000 1000-1500 >1500


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% autopsies in pts with cancer positive for IFI

80

Data from 8 studies

All IFI

40

ASPERGILLUS

1950

1970

1990


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FEBRILE NEUTROPENIA AND IFI

92 patients with febrile neutropenia

panfungal PCR q weekly

34 PCR +ve

Hebart et al Br J Haematol 2000


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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


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IA IN STEM CELL RECIPIENTS

% cumulative

incidence 12%

4%

19901998

Marr et al Abstract #2001 ASH 2001


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IA in Hematological PatientsOutcome

222 studies

> 1995

50 studies

Case fatality rate %

Lin et al CID 2001


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Management of IA

AMBISOME

10 drug

Immune-modulation

surgery

20 drug


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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


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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


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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


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IPA

CAB 0.5mg

CAB 0.8mg

CAB DC

CAB 0.3mg

Day 1 4 7 10

2cms/day in vitro


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Liposomal Amphotericin B

  • Infrequent toxic related dosing limitations

  • Less indication for steroids, opiates

  • Short infusion time

  • Dose escalation possible


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Liposomal versus conventional amphotericin B

Animal data

Human open trial

Prospective clinical and other


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Liposomal versus conventional amphotericin B

Intratracheal inoculation

Neutropenic rabbits

% lobes infected

Francis et al JID 1994


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LIPOSOMAL VERSUS CONVENTIONAL AMPHOTERICIN B: SURVIVAL

100%

Rx none CAB1 LAB1 LAB5 LAB10

Francis et al JID 1994


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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


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Concentration dependency

  • g/ml and log cfu/g

Groll et al JID 2000


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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


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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



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AmBisome optimal dosing

  • Animal candida thigh infection model

  • Neutropenic animal models

  • Previous human observations

  • In depth case studies

  • Histopathologic

Maximum tolerated dose


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LIPOSOMAL VERSUS CONVENTIONAL AMPHOTERICIN B: SURVIVAL

100%

Rx none CAB1 LAB1 LAB5 LAB10

Francis et al JID 1994


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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


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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



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EORTC 19923 SURVIVAL

100%

1 MG

4 MG

Log rank p = 0.58

0 1 2 3 4 5 6 months



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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.


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Hepatic candidiasis

CANDIDA ANTIGEN

CANDIDA ANTIBODY

30

1.5

1.0

10

0.5


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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


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IPA early diagnosis-AmBisome treatment link

HALO SIGN

The radiologic counterpart of the histopathologic early IPA lesion


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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


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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



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ARNF TO 1ST +VE SCAN

MEDIAN


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IPA early diagnosis-AmBisome treatment link

%

100

50

LINKED

RESPONSE

LITERATURE

CRUDE MORTALITY

ATTRIB MORTALITY

0


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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


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CT SERIES IPA FROM DAY 16 ARNF

PATIENT HAS AIR CRESCENT IN RUL, STARTS TREATMENT WITH AMBISOME

DAY 16

DAY 30

DAY 120


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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


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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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