Ten years experience of liposomal amphotericin B, AmBisome treatment in

solid organ transplant recipients(SOT)

Our experience with AmBisome More than 10 years experience in 383 patients. Two double blind placebo controlled randomized

trials with AmBisome as prophylaxis Allogeneic & autologous BMT Liver transplant recipients

Three Retrospective analyses of treatment with respect to safety and efficacy Allogeneic BMT recipients (5 years) (79 patients) Solid organ transplant recipients (10years) (196 patients) Child recipients of transplant (7 years) (61 patients)

Fungal Infections - Morbidity /Mortality

Invasive fungal infections contribute to the morbidity and mortality in SOT recipients.

_ Reported incidence: up to 53 % _ Kidney 0 - 20 %_ Liver 4 - 42 %_ Pancreas 6 - 38 %_ Heart/lung 10 - 35 %_ Small bowel 33 - 53 %

_ Reported mortality: up to 77 % for Candidosisup to 100 % for Aspergillosis

Incidence of invasive fungal infections at our center during the time periods 1989 to 1994 & 1996

Organ n V*FI Incid S** FI Incid

Liver 240 21 9% 17 16 %

Kidney 540 5 1% 16 4 %

Kidney &

Pancreas 38 1 3% 9 26 %

BMT 199 17 9% 41 29 %

*VFI = verified fungal infection

**SFI = suspected fungal infection

AmBisome prophylaxis

Liver transplant recipients

Transplantation. 59: 1: 45-50, 1995.

Transplant. Proc.27: 1195-1198, 1995.

Study Design LTX prophylaxis

Double blind randomized, placebo controlled study 86 patients were randomized

Prophylactic treatment : Treatment group : AmBisome, 1 mg/kg daily i.v. Control group : Equal volume of placebo drug i.v. Treatment during days 1 to 5 posttransplant

Evaluation criteria for efficacy: 77 patients who recieved all 5 days of prophylaxis

Results Adverse Events LTX prophylaxis all 84 patients

Time Relation AmBisome Placebo

Certain 1 Lumbago Non

Early

Possible 1 Trombocytopenia1 Trombocytopenia and nephrotoxicity

1 Hepato-toxicity

Late Non Non

Results invasive fungal infections after prophylaxis in LTX, first year

Time AmBisomen= 40

Placebon= 37

Early (days 5 to 30)(probability)

0(0 %)

6(16 %)

Late (month 1 to 12)(probability)

4(11 %)

5(17 %)

Total (year 1)(probability)

4(11 %)

11(29 %)

p<0.01

p<0.05

LTX prophylaxis; Results early FI : Placebo group

Invasive fungal infections_ 5 Candida albicans inf: 4 peritonitis - abdomen cultures

1 fungemia - blood cultures_ 1 Aspergillus niger inf: Pneumonia - BAL culture + biopsy

_ Median day to FI : 12 (range 6 - 20)_ All patients recieved treatment and 5 survived

LTX prophylaxis; Results late FI : Placebo group

Invasive fungal infections_ 4 Candida albicans inf: 1 peritonitis - abdomen cultures

3 disseminated - autopsy findings_ 1 Aspergillosis: Disseminated - autopsy finding

_ Median day to FI : 150 (range 41 - 365)_ 2 of 5 patients recieved treatment and 1was cured

LTX prophylaxis; Results late FI : AmBisome group

Invasive fungal infections_ 3 Aspergillus spp inf: 1 pneumonia – autopsy findings

2 disseminated – autopsy findings_ 1 Candida albicans: Cholangitis - cultures

_ Median day to FI : 81 (range 39 - 325)_ 1 of 4 patients recieved treatment and was cured

AmBisome treatment

Solid organ transplant recipients,

10 year data

SOT patients Patients treated between Jan 1989 - March 1999 196 solid organ transplant recipients 220 episodes of AmBisome treatment

56 for a verified infections 79 for a suspected infections 85 as prophylaxis

106 males 90 females Median age was 42 years, range 1 - 72

SOT patients

123 liver (LTX) transplant recipients 3 liver and bone marrow transplant recipients 5 liver and kidney transplant recipients 42 kidney (KTX) transplant recipients 21 kidney & pancreas (KPTX) transplant recipients 1 kidney and insulin islet transplantation recipient 1 pancreas (P) transplant recipients

AmBisome treatment data in SOT

Fungal Infection

AmBisome treatment Verified Suspected Prophylactic

Duration (days),

mean ± SD (median) 23±17(18) 18±15 (14) 16±19 (7)

range 4-81 1-80 1-83

Max. dose (mg),

mean ± SD (median) 2.0±1 (1.8) 1.7±0.9 (1.4) 1.4±0.8 (1.0 )

range 0.7-5.5 0.7-5 0.6-6

Total dose (g),

mean ± SD (median) 1.7±1.7 (0.95) 1.4±1.3 (1.1) 0.6±0.5 (0.4)

range 0.05-8.1 0.06-8 0.03-2.4

Days with AmBisome

Upper Boundaries

No

of o

bs

0

5

10

15

20

25

30

35

40

45

50

55

60

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85

AmBisome dose (mg/kg/d)

Upper Boundaries

No

of o

bs

0

5

10

15

20

25

30

35

40

45

50

55

60

65

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

2,2

2,4

2,6

2,8

3,0

3,2

3,4

3,6

3,8

4,0

4,2

4,4

4,6

4,8

5,0

5,2

5,4

5,6

5,8

6,0

Total dose AmBisome (gram)

Upper Boundaries

No

of o

bs

0

10

20

30

40

50

60

70

80

90

100

0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 4,0 4,5 5,0 5,5 6,0 6,5 7,0 7,5 8,0 8,5

Adverse events in SOT 335 adverse events were reported 9 (3%) were regarded as caused by AmBisome treatment

6 Lumbago 2 Lumbago combined with chills 1 Lumbago with dyspnea

No anaphylactic reaction was reported 224 (67%) of the adverse events were regarded as

probably related to AmBisome 112 (33%) of the adverse events were regarded as not

related to AmBisome

Kidney function before, during and after AmBisome treatment measured as S-creatinine

150

170

190

210

230

250

Before During After

Mean+SE

Mean-SE

Mean

umol/L

Efficacy; Suspected FI in SOT

75 patients recieved 79 episodes of treatment for suspected FI

57 patients survived with clearance of symptoms and 10 died with no FI at autopsy

7 patients died, no autopsy was performed 1 patient died with FI at autopsy (Aspergillus. fum) Efficacy was shown in 67 out of 75 patients, 89 %

Proven invasive fungal infections in SOT

A total of 56 proven infections were treated in 50 patients

38 LTX, 7 KTX and 5 KPTX recipients 20 cholangitis (18 C. alb, 1 C. parapsilosis & 1 C. glabrata) 14 perotonitis (13 C. albicans & 1 C. pelliculosa ) 14 fungemias (13 C. albicans & 1 C. glabrata) 4 pneumonias (2 Asp. sp, 1 C. alb + glab, 1 C. alb.) 3 disseminated inf. (C. alb.) 1 urinary tract infection (C. alb)

Efficacy, proven invasive fungal infections in SOT

Out of 50 patients with proven infections; 14 patients died 10 were FI negative at autopsy 3 was positive for fungi at autopsy 1 was not autopsied

Survival or mycotic clearance was found in 46 out of 50, 92% of the patients

Conclusion solid organ transplantation

10 years experience of Ambisome treatment in solid organ transplant recipients at one single center has revealed:

AmBisome treatment was safe AmBisome treatment was efficacious as seen as

survival or mycotic clearance in 92% of proven fungal infections in SOT patients

Efficacy in suspected FI was 89 % clinical cures

General conclusion; prophylaxis & treatment in transplantation

Prophylaxis with AmBisome Efficacious in Liver transplantation

Treatment with AmBisome Efficacious and safe in solid organ

transplantation