INVASIVE ASPERGILLOSIS

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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
• Surgery Repetitive/extensive

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Neutropenia risk
50 0
Duration of neutropenia
Risk infection/1000 days
Neutrophils lt100 100-500 500-1000
1000-1500 gt1500
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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
• 1990 1998

Marr et al Abstract 2001 ASH 2001
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IA in Hematological PatientsOutcome

• 222 studies
• gt 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 199638215
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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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CAB v LAB responses
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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
N 1
0.5 MG
1- 1.5 MG
N 14
0/1 SURVIVAL
13/14
Burgh J Clin Oncol 198751985
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EORTC 19923 probable/proven IPA
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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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Proven IPA
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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

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1.5
1.0
10
0.5
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Hepatic candidiasis
LAB 5mg
CASPOFUNGIN
LAB 10mg
LIVER image
39 38 39 39 38
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TEMP
400 110 150 190
100 30 15
CRP
1 21 25
42 56
70
DAY Rx
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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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(No Transcript)
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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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DISTRIBUTION OF CT FINDINGS
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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