Ten years experience of liposomal amphotericin B, AmBisome ...
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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