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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

INVASIVE ASPERGILLOSIS

Management with liposomal amphotericin B

Michael Ellis

ipa ifi the intrinsic setting
IPA/IFI – THE INTRINSIC SETTING
  • Leukemia
  • Cancer
  • Multiple myeloma
  • Malnutrition
ipa ifi the extrinsic setting
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
slide4

Neutropenia risk

50

0

Duration of neutropenia

Risk infection/1000 days

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

slide5

% autopsies in pts with cancer positive for IFI

80

Data from 8 studies

All IFI

40

ASPERGILLUS

1950

1970

1990

febrile neutropenia and ifi
FEBRILE NEUTROPENIA AND IFI

92 patients with febrile neutropenia

panfungal PCR q weekly

34 PCR +ve

Hebart et al Br J Haematol 2000

ipa in prolonged neutropenia
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

ia in stem cell recipients
IA IN STEM CELL RECIPIENTS

% cumulative

incidence 12%

4%

19901998

Marr et al Abstract #2001 ASH 2001

ia in hematological patients outcome
IA in Hematological PatientsOutcome

222 studies

> 1995

50 studies

Case fatality rate %

Lin et al CID 2001

management of ia
Management of IA

AMBISOME

10 drug

Immune-modulation

surgery

20 drug

slide11

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

slide12

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

slide13

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

slide14

IPA

CAB 0.5mg

CAB 0.8mg

CAB DC

CAB 0.3mg

Day 1 4 7 10

2cms/day in vitro

liposomal amphotericin b
Liposomal Amphotericin B
  • Infrequent toxic related dosing limitations
  • Less indication for steroids, opiates
  • Short infusion time
  • Dose escalation possible
liposomal versus conventional amphotericin b
Liposomal versus conventional amphotericin B

Animal data

Human open trial

Prospective clinical and other

liposomal versus conventional amphotericin b17
Liposomal versus conventional amphotericin B

Intratracheal inoculation

Neutropenic rabbits

% lobes infected

Francis et al JID 1994

slide18

LIPOSOMAL VERSUS CONVENTIONAL AMPHOTERICIN B: SURVIVAL

100%

Rx none CAB1 LAB1 LAB5 LAB10

Francis et al JID 1994

slide19

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

slide20

Concentration dependency

  • g/ml and log cfu/g

Groll et al JID 2000

liposomal versus conventional amphotericin b21
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

cab v lab
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

ambisome optimal dosing
AmBisome optimal dosing
  • Animal candida thigh infection model
  • Neutropenic animal models
  • Previous human observations
  • In depth case studies
  • Histopathologic

Maximum tolerated dose

slide25

LIPOSOMAL VERSUS CONVENTIONAL AMPHOTERICIN B: SURVIVAL

100%

Rx none CAB1 LAB1 LAB5 LAB10

Francis et al JID 1994

treatment failure in ipa and tissue drug levels
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

slide27

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

slide29

EORTC 19923 SURVIVAL

100%

1 MG

4 MG

Log rank p = 0.58

0 1 2 3 4 5 6 months

eortc 19923 summary
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.

slide32

Hepatic candidiasis

CANDIDA ANTIGEN

CANDIDA ANTIBODY

30

1.5

1.0

10

0.5

slide33

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

ipa early diagnosis ambisome treatment link
IPA early diagnosis-AmBisome treatment link

HALO SIGN

The radiologic counterpart of the histopathologic early IPA lesion

ipa early diagnosis ambisome treatment link36
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

ipa early diagnosis ambisome treatment link37
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

ipa early diagnosis ambisome treatment link40
IPA early diagnosis-AmBisome treatment link

%

100

50

LINKED

RESPONSE

LITERATURE

CRUDE MORTALITY

ATTRIB MORTALITY

0

ipa early diagnosis ambisome treatment link41
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

ct series ipa from day 16 arnf
CT SERIES IPA FROM DAY 16 ARNF

PATIENT HAS AIR CRESCENT IN RUL, STARTS TREATMENT WITH AMBISOME

DAY 16

DAY 30

DAY 120

slide43

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

ipa early diagnosis ambisome treatment link44
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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