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

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  • Our long experience with Liposomal Amphotericin B (AmBisome) at the department of Transplantation surgery, Huddinge University Hospital, Karoliska Institute, Stockholm, Sweden. We started to use AmBisome within a compassionate trial during 1989 in both Allogeneic stem cell transplant recipients as well as within solid organ transplant recipients. Later on we initiated two randomised placeo controlled prophylactic trials among stem cell and liver transplant recipients. We have also evaluated both safety as well as efficacy among our patients.
  • This slide shows international published incidence and mortality figures of invasive fungal infections among solid organ transplant recipients. At present the incidence among kidney recipients is more or less around 0 % uless the patient is diabetic. The majority of infections are seen among liver and small bowel transplant recipients, but as you can see, bothe heart/lung and pancreas transplant recipients are at high risk for an infection. An intresting finding is that mortality is high, aslo in modern papers. In general the feeling among physicians are that these patients usually do not die of but with the infection, thus complicating the course. However, the mortality figures in some extent dismiss this and reveal the infection as a much more serious event.
  • The incidence of both proven as well as suspected invasive fungal infections we found among our patients during a five year for stem cell and seven year period for solid organ transplant recipients.
  • The design of our double blind placebo controlled randomised phrophylactic trial in liver tarnsplant recipients. This trial was done together with Prof Christer Höckerstedt at Fouth Department of Surgery and Childrens Hospital, Helsinki University Central Hospital, Helsinki, Finland. In all 86 patients were randomised, 59 in Sweden and 27 in Finland, 1 patient died during surgery and in one no data was collected, thus 84 patients did enter the trial and were evaluated for safety. For efficacy 77 patients who recieved all 5 days of AmBisome prophylaxis were evaluated.
  • 1 Adverse events reported during the study, remember that AmBisome prophylaxis was only given for the first 5 days Side effects were only seen early, during the first month post-transplant, later during the following year no adverse event was reported. In liver transplant recipients an not uncommon adverse event is backpain, which usually resolves if infusion time is prolonged.
  • 2 AmBisome prophylaxis was effective both during the first month with no infection in the AmBisome arm compared to 6, 5 caused by Candida and 1 caused by Aspergillus in the placebo arm. Also in the long run, during the first year after transplantation prophylaxis had an impact on fungal infections, with 5 more infections developing in the placebo arm compared to 4 among the AmBisome treated patients. An interesting finding here was that we had a different infection panorama (see following slides) with more Candida infections in the placebo arm and Aspergillus infections in the AmBiosme arm. This could be interpreted as that Candida infections develop or becomes latent during the initial surgical procedure but aspergillosis develops anytime mainly from inhalation of spores, which you cant prevent by the initial 5 days of prophylaxis..
  • 3 Early fungal infections in the placebo group. Only one patient with a fungal infection died. This patient suffered from Candida peritonitis, he recieved treatment for 9 days (850 mg intotal dose) and died 28 days later in heamorrages, without any findings of fungi at autopsy.
  • 4 Late fungal infections in the placebo group, all but one patient died. The patient who survived suffered from Candida peritonitis and recieved 54 days of teatment. This fact reveals the high mortality in Candida infections seen in liver transplant recipients, since several of these infections were first acknowleged at autopsy.
  • 5 Late fungal infections in the AmBisome group, all patients with aspergillosis died, as a matter of fact the infections were first seen at autopsy. The patient who survived suffered from Candida cholangitis and abcess formation which was cured after 67 days of teatment.
  • We performed a retrospective analysis of our first ten years of AmBisome treatment in solid organ transplant recipients. Patient charts were retrospectivly analysed for adverse events and efficacy.
  • The majority of patients treated were liver transplant recipients, some in conjunction with stem cell or kidney transplants.
  • We examined treatment data in the different groups of patients according to prophylaxis or if the fungal infection was suspected or verified. Interestingly enough treatment for verified fungal infections was not extreme, the median total dose was 0.95 g, median max dose of 1.8 mg/kg/day for a median of 18 days, however, the ranges were wide.
  • The distribution of lenght of AmBisome treatment, revealing that few patients recieved more than one month of treatment.
  • The distribution of maximum doses, the majority recieved below 2 mg/kg/day, but up to 6 mg/kg/day was given without toxicity problems.
  • The distribution of total doses given reveal that the majority of patients recieved a low total dose, this is due to the fact that prophylaxis is included.
  • This slide show adverse events as found during the retrospective analysis, the majority of findings are laboratory values exceeding the normal ranges. Only 9 that is 3% of reported adverse events were considered caused by AmBisome, mainly backpain as have been discussed earlier.
  • Kidney function was no problem as indicated by this slide, the upper normal value is 120 umol/l, thus indicating that kidney function was impaired already before start of AmBisome treatment. A transient increase of S-Creatinine during treatment, was sen but, 24 hours after treatment kidney function was even lower than before treatment. At our unit we tend disregard kidney function when dosing AmBisome.
  • In patients with a suspected fungal infection, 18 out of 75 patients died, 10 with no trace of fungi at autopsy. Only one patient died with fungi at autopsy, but, 7 more died without any autopsy, thus the efficacy was 89% as indicated by clinical cures.
  • This slide lists verified invasive fungal infections, the majority in liver transplant recipients and mainly caused by various Candida spp.
  • Efficacy figures presented as survival or mycological cures in proven invasive infections, The sucessrate of 92% is most encouraging.
  • We have come a long way in prophylaxis, handling and treating invasive fungal infections in solid organ transplant recipients during the ten years AmBisome been available. Mortality figures have been reduced from around 77 - 100% to below 10% which is encouraging.
  • Transcript

    • 1. Ten years experience of liposomal amphotericin B, AmBisome treatment in solid organ transplant recipients (SOT)
    • 2. 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)
    • 3. 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 Candidosis up to 100 % for Aspergillosis
    • 4. 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
    • 5. AmBisome prophylaxis Liver transplant recipients Transplantation. 59: 1: 45-50, 1995. Transplant. Proc.27: 1195-1198, 1995.
    • 6. 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
    • 7. Results Adverse Events LTX prophylaxis all 84 patients
    • 8. Results invasive fungal infections after prophylaxis in LTX, first year p<0.01 p<0.05
    • 9. 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
    • 10. 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
    • 11. 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
    • 12. AmBisome treatment Solid organ transplant recipients, 10 year data
    • 13. 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
    • 14. 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
    • 15. 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
    • 16. Days with AmBisome
    • 17. AmBisome dose (mg/kg/d)
    • 18. Total dose AmBisome (gram)
    • 19. 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
    • 20. Kidney function before, during and after AmBisome treatment measured as S-creatinine
    • 21. 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 %
    • 22. 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 )
    • 23. 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
    • 24. 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
    • 25. General conclusion; prophylaxis & treatment in transplantation
      • Prophylaxis with AmBisome
        • Efficacious in Liver transplantation
      • Treatment with AmBisome
        • Efficacious and safe in solid organ transplantation

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