a Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, UK b Department of Pathology, Queen Elizabeth Hospital, Birmingham B15 2TH, UK c Department of Microbiology, Queen Elizabeth Hospital, Birmingham B15 2TH, UK
Abstract
We reviewed the use of liposomal amphotericin B in 30 patients receiving therapy following liver transplantation over a 2 year period. Five of these patients were treated for presumed invasive aspergillosis: four of them died despite therapy, each having combined renal and respiratory failure at the time of diagnosis of presumed aspergillosis. Post-mortem examination of three of these patients confirmed the diagnosis of aspergillosis. Twenty-five patients were treated empirically; 11 died and supportive evidence for invasive fungal infection following commencement of therapy was found in only one case. Following liver transplantation, the use of liposomal amphotericin B following confirmation of aspergillus infection or for empirical therapy is of uncertain value, and strategies based on selective prophylaxis for high-risk cases may be preferable.
Introduction
Invasive fungal infection is an important complication of liver transplantation and is associated with a high mortality despite antifungal therapy. Risk factors for infection are well defined. Candida spp. and Aspergillus spp. are the most common fungal pathogens in this setting, and aspergillus infections are associated with the higher mortality. 1234 Fluconazole prophylaxis is widely used and may be helpful in prevention of invasive candidiasis but will not protect against aspergillosis.5 AmBisome (Vestar Ltd, Cambridge, UK), a liposome-encapsulated formulation of amphotericin B, has broad antifungal activity and has reduced toxicity compared with amphotericin B in deoxycholate solution, allowing higher doses to be given. It may, therefore, have an important role for the treatment and prophylaxis of fungal infections including those occurring in liver transplant recipients.6,7 We used liposomal amphotericin B in selected cases from January 1994 to December 1995, and here review our experience.
Materials and methods
Patients
During the study period, 262 adult patients underwent liver transplantation. All patients received immunosuppressive therapy with corticosteroids, cyclosporin, and azathioprine. Antibacterial prophylaxis was given for 48 h following transplantation. Oral nystatin (500,000 units tds) and amphotericin B (100 mg tds) were given for 3 months following transplantation. In addition oral fluconazole (100 mg daily) was given as prophylaxis to patients transplanted for fulminant liver failure and to patients requiring prolonged antibacterial therapy. (>72 h). Liposomal amphotericin B (AmBisome) therapy (3 mg/kg) was commenced for suspected invasive fungal infection. Clinical criteria for commencing AmBisome included respiratory sepsis unresponsive to antibacterials, unexplained neurological signs, unexplained fever, or leucocytosis unresponsive to antibacterials. Supporting laboratory criteria for commencing AmBisome included isolation of Aspergillus spp. from any site, or isolation of Candida spp. from blood or normally sterile sites. Isolation of Candida spp. from superficial mucosal sites or sputum alone was not considered diagnostic of invasive candidiasis.
Analysis
Case notes of all liver transplant recipients receiving AmBisome therapy were reviewed and the following information documented: indication for transplantation; indication for AmBisome therapy; any positive fungal cultures before or during therapy; dosage and duration of therapy; renal function at onset and end of therapy; adverse reactions; and post-mortem findings. Indications for AmBisome therapy were categorized as presumed aspergillosis (a positive culture for Aspergillus spp. from any site) or empirical therapy (no positive fungal isolates from blood or other normally sterile sites, but clinical suspicion of invasive fungal infection according to the criteria listed above).
Results
Thirty patients received AmBisome during the study period; indications for therapy are shown in Table I. The median duration of therapy was 10 days (range 146 days). The median dosages used were 3.2 (range 2.83.5) mg/kg daily for presumed aspergillosis and 2.1 (range 1.82.4) mg/kg daily for empirical therapy of suspected fungal infection.
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Five patients had repeatable positive cultures for Aspergillus spp. before starting AmBisome therapy (patients 15, Table II). At the time of isolation, all had respiratory failure requiring mechanical ventilation and four were receiving renal support in the form of continuous veno-venous haemofiltration (CVVH). Four of the five patients had positive sputum cultures whilst the fifth had positive wound drainage cultures. Three of the five had had second laparotomies or early regrafting. In all cases AmBisome was started following the first positive cultures for Aspergillus spp. The four patients with combined renal and respiratory failure died despite therapy. The sole survivor had respiratory but not renal failure at the time of aspergillus isolation. Three of the four patients who died underwent post-mortem examination; in each case invasive pulmonary aspergillosis was confirmed and in two cases this had disseminated to other organs (Table II).
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Twenty-five patients received empirical AmBisome therapy for clinically suspected invasive fungal infection. Five of these 25 patients had positive cultures for Candida albicans from sputum before AmBisome therapy; three of these five initially received fluconazole therapy, followed by AmBisome when their clinical condition deteriorated. No patient had further isolation of C. albicans during fluconazole or AmBisome therapy and none had any other fungal isolates from sputum or other sites (including broncho-alveolar washings in three cases) during or following AmBisome therapy. Two of these five patients died despite therapy; one underwent post-mortem examination and no evidence of fungal infection was found on histopathological examination.
One patient given empirical AmBisome therapy had a positive culture for Aspergillus fumigatus following commencement of therapy (patient 6, Table II). This patient was extubated on the third post-operative day and was treated with OKT3 for refractory acute rejection on day 10. He developed acute renal failure requiring CVVH from day 11, at which point AmBisome was commenced. A. fumigatus was isolated from his sputum 5 days later, but the patient eventually made a full recovery following 16 days of therapy.
Of the remaining 19 patients who received empirical AmBisome therapy, 15 were culture-negative for fungi and four were colonized with Candida spp., not from sputum samples but from throat swabs or stool specimens only, before AmBisome therapy. There were no other fungal isolates during AmBisome therapy, including from four patients who underwent broncho-alveolar lavage. Head CT scans were performed in five patients with unexplained neurological deterioration and in all cases revealed ischaemic changes only; none had intracranial mass lesions. Nine of these 19 patients died and post-mortem examination was performed in six cases; four had bronchopneumonia but fungal infection was excluded in all cases.
Toxicity
No adverse reactions attributable to AmBisome therapy were noted (data not shown).
Discussion
This retrospective review demonstrates the continuing high mortality associated with aspergillus infections following liver transplantation. All six patients developing aspergillosis were at high risk for such infections, as defined previously by the presence of renal failure, repeat laparotomy or regraft following transplantation, use of immunosuppressive therapy before transplantation, and intensive post-operative immunosuppressive therapy for graft rejection. 1,2,3 We used recommended doses of AmBisome (3 mg/kg daily) while continuing immunosuppressive therapy. All patients with both respiratory and renal failure at the time of aspergillus isolation subsequently died. The diagnosis of invasive aspergillosis was confirmed by tissue diagnosis at post-mortem in three of the cases. In the remaining three cases, at least two positive cultures of Aspergillus spp. were obtained from the same site. which is recognized as highly suggestive of invasive disease.1,3
Patients who had positive cultures for Candida spp. before empirical AmBisome therapy was commenced were difficult to define in terms of infective pathology, since mucosal colonization with Candida spp. is relatively common following transplantation. 4 None of these patients had candida isolated from sterile sites, including blood and bronchial washings, and there was no post-mortem evidence of invasive fungal infection.
Our strategy of prescribing AmBisome to patients with clinical suspicion of fungal infection or with positive cultures of Aspergillus spp. (any site) or Candida spp. (sterile sites) proved relatively ineffective. Although difficult to confirm retrospectively, we feel many patients treated on the basis of clinical suspicion were of only low or moderate risk of invasive fungal infection, and probably received AmBisome at 3 mg/kg unnecessarily. On the other hand, in the cases of proven aspergillosis, four of six patients died. There are several reasons why AmBisome therapy may have failed. The recommended dosage of 3 mg/kg daily may be suboptimal; dosages of up to 5 mg/kg daily have been tolerated and used successfully in the treatment of invasive aspergillosis.7 Furthermore, immunosuppressive therapy was continued during AmBisome therapy; where therapy for acute rejection has preceded fungal infection this may be necessary, but otherwise it might be appropriate to reduce or stop immunosuppressive therapy.
There is little consensus on the most effective antifungal strategy in liver transplantation. The use
of enteral non-absorbable nystatin and/or amphotericin B prophylaxis reduces gastrointestinal
colonization with Candida spp. but has not been shown to reduce invasive fungal
infections.8,9
Fluconazole is relatively safe and inexpensive, and has been shown to be generally effective in
prevention of candidiasis.5,10,11 However, the main challenge remaining is
to find an agent (or agents) that is safe and cost effective in the prevention of aspergillosis. Oral
itraconazole may have a role in therapy or prevention of aspergillosis,12 but has not been used as prophylaxis in liver transplantation; gastrointestinal
side-effects are problematic and there is no parenteral form. Parenteral amphotericin B in a low
dosage of 0.5 mg/kg daily may avoid the toxicity of the full therapeutic dosage, but may be
ineffective as prophylaxis.13 Liposome-encapsulated or
lipid-associated amphotericin B at appropriate dosage, targeted at appropriate high-risk patients
at an early stage, may be the most effective approach. It has been demonstrated that a
prophylactic 5 day course of AmBisome for all patients undergoing liver transplantation is
successful in preventing fungal infections,6 but a more
cost-effective regimen may be achieved with fluconazole for most cases, reserving prophylactic
iv amphotericin B for defined high-risk groups. Our experience that recommended dosage of
AmBisome is ineffective for patients with established aspergillus infection in the setting of
multiorgan failure and continued immunosuppressive therapy after liver transplantation has led
us to adopt the following strategy. We commence lipid- associated amphotericin B (3 mg/kg
daily) prophylactically on day 5 post-operatively for patients who require prolonged (5
days)
intensive care following liver transplantation. This includes all patients who have or develop
renal or respiratory failure, and all patients who have had early repeat laparotomies or regrafting.
References
1 . Collins, L. A., Samore, M. H., Roberts, M. S., Luzzati, R., Jenkins, R. L., Lewis, W. D. et al. (1994). Risk factors for invasive fungal infections complicating orthotopic liver transplantation. Journal of Infectious Diseases 170, 64452.[ISI][Medline]
2 . Castaldo, P., Stratta, R. J., Wood, P., Markin, R. S., Patil, K. D., Shaefer, M. S. et al. (1991). Clinical spectrum of fungal infections after orthotopic liver transplantation. Archives of Surgery 126, 14956.[Abstract]
3 . Kusne, S., Torre-Cisneros, J., Manez, R., Irish, W., Martin, M., Fung, J. et al. (1992). Factors associated with invasive lung aspergillosis and the significance of positive Aspergillus culture after liver transplantation. Journal of Infectious Diseases 166, 137983.[ISI][Medline]
4 . Tollemar, J., Ericzon, B. G., Holmberg, K. & Andersson, J. (1990). The incidence and diagnosis of invasive fungal infections in liver transplant recipients. Transplantation Proceedings 22, 2424.[ISI][Medline]
5 . Kung, N., Fisher, N., Gunson, B., Hastings, M. & Mutimer, D. (1995). Fluconazole prophylaxis for high-risk liver transplant recipients. Lancet 345, 12345.[ISI][Medline]
6 . Tollemar, J., Hockerstedt, K., Ericzon, B. G., Jalanko, H. & Ringden, O. (1995). Liposomal amphotericin B prevents invasive fungal infections in liver transplant recipients. A randomized placebo- controlled study. Transplantation 59, 4550.[ISI][Medline]
7 . de Marie, S., Janknegt, R. & Bakker-Woudengerg, I. A. J. M. (1994). Clinical use of liposomal and lipid-complexed amphotericin B. Journal of Antimicrobial Chemotherapy 33,907 16.[Abstract]
8 . Rossi, G., Tortorano, A. M., Viviani, M. A., Pagano, A., Colledan, M., Fassati, L. R. et al. (1989). Aspergillus fumigatus infections in liver transplant patients. Transplantation Proceedings 21, 226870.[ISI][Medline]
9 . Wiesner, R. H., Hermans, P. E., Rakela, J., Washington, J. A., Perkins, J. D., DiCecco, S. et al. (1988). Selective bowel decontamination to decrease Gram-negative aerobic bacterial and candida colonisation and prevent infection after orthotopic liver transplantation. Transplantation 45, 5704.[ISI][Medline]
10 . Goodman, J. L., Winston, D. J., Greenfield, R. A., Chandraseker, P. H., Fox, B., Kaizer, H. et al. (1992). A controlled trial of fluoconazole to prevent fungal infections in patients undergoing bone marrow transplantation. New England Journal of Medicine 326, 84551.[Abstract]
11
.
Rex, J. H., Bennett, J. E., Sugar, A. M., Pappas, P. G.,
Van der Horst, C. M., Edwards, J. E. et al. (1994). A randomised trial
comparing fluconazole with amphotericin B for the treatment of candidemia in patients without
neutropenia. New England Journal of Medicine 331, 132530.
12 . Denning, D. W., Lee, J. Y., Hostetler, J. S., Pappas, P., Kauffman, C. A., Dewsnup, D. H. et al. (1994). NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis. American Journal of Medicine 97, 13544.[ISI][Medline]
13 . Singh, N., Mieles, L., Yu, V. L. & Gayowski, T. (1993). Invasive aspergillosis in liver transplantation recipients: association with candidaemia and consumption coagulopathy and failure of prophylaxis with low-dose amphotericin B. Clinical Infectious Diseases 17, 9068.[ISI][Medline]
Received 18 August 1997; returned 16 April 1998; revised 31 July 1998; accepted 24 November 1998