Division of Clinical Haematology, Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni Ma Claret, 167, 08025 Barcelona, Spain
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Abstract |
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Introduction |
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Patients and methods |
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All 10 had received c-AmB, which was discontinued due to nephrotoxicity, oliguria or infusion-related toxicities. One patient (case 8) received ABLC without prior systemic antifungals because of a history of nephrotoxicity to c-AmB and the concomitant use of several other nephrotoxic drugs. Four patients had also received fluconazole either as prophylaxis or for treating an oropharyngeal candidosis.
ABLC (ABELCET, PENSA, Grupo Esteve, Barcelona, Spain) was provided by the hospital pharmacy and was initially infused iv over 1 to 2 h. Premedication was routinely given with diphenhydramine and hydrocortisone. Complete response to ABLC was defined as resolution of all attributable pretreatment signs and symptoms of the invasive mycosis by the end of therapy. Substantial reduction of these findings by the end of therapy or death but without complete resolution was considered a partial response, and failure was defined as no change or worsening of the pretreatment signs and symptoms of the infection.
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Results and discussion |
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Of the 10 patients, four died during therapy between 11 and 34 days after the start of ABLC, but in only one case was progressive aspergillosis a contributing factor to death (case 8, see Table). Two of these patients had severe refractory graft-versus-host disease (cases 5 and 8), and the other two died after a prolonged pancytopenia (cases 4 and 7). Five patients showed complete response to ABLC, including three cases of pulmonary aspergillosis and the two patients with candidosis. One further patient with invasive aspergillosis showed a partial response due to residual lung infiltrates on thoracic CT scan after treatment. In all five neutropenic patients, the neutrophil count recovered during treatment. After 16 to 45 days of ABLC, antifungal therapy was continued for various times with itraconazole or fluconazole in four cases.
In a recent report by Walsh et al.3 including 556 patients, 48% of infections with filamentous fungi and 70% of yeast infections responded to ABLC, although these data were based on a USA multicentre salvage protocol which included heterogeneous groups of patients. The standard dosage of ABLC in these and other studies was 5 mg/kg/day, based on experimental animal data and on the pharmacokinetics of ABLC in humans. With respect to this latter point, the serum levels of AmB following an iv dose of ABLC are lower than equivalent doses of c-AmB and in particular, liposomal AmB.5,6 Although this may suggest that higher doses are thus needed to reach therapeutic levels in infected organs, this may not be the case since antifungal efficacy may depend more on the concentrations of AmB reached in target organs than in peripheral blood. In this respect, treatment with ABLC leads to very high levels of AmB in liver, spleen and lungs compared with blood and kidneys, probably the result of rapid clearance of the drug by the reticuloendothelial system.6
Our results suggest that lower doses of ABLC may be equally effective and less toxic than
higher doses in treating aspergillosis and candidosis in adults with haematological malignancies
and an invasive mycosis. There have been few previous studies with low-dosage ABLC for
various indications. In the study by Walsh et al.,3
72 patients received ABLC at a dosage of 3 mg/kg/day, but their results were reported with
the rest since efficacy and toxicity were said to have been similar to the others receiving the
higher dose. These patients, however, were described separately by Linden,7 showing a response rate (complete and partial) of 82%. Additionally, a 78%
(28/36) response rate for coccidioidomycosis treated with 0.62.5 mg/kg/day ABLC7 and a 62% (8/13) response for cryptococcal meningitis
treated with 1.22.5 mg/kg/day8 have been reported.
Recently, Walsh et al.9 described the clinical
outcome and AmB pharmacokinetics in six children with leukaemia and chronic systemic
candidosis treated with 2.5 mg/kg/day ABLC, with complete response in all (5/5) evaluable
cases. Finally, investigators from India have reported a randomized trial of treatment of visceral
leishmaniasis with a 5-day course of ABLC at dosages of 1, 2 or 3 mg/kg/day, with responses in
all cases, irrespective of the dose given.10 Since visceral
leishmaniasis affects predominantly the bone marrow, liver and spleen, this result also suggests
that high tissue levels of AmB are reached with a brief course of ABLC at low doses.6,10
In conclusion, our results and those of others suggest that ABLC at dosages of 23 mg/kg/day may be as effective but less toxic and expensive than the approved dosage of 5 mg/kg/day in the treatment of adults with a haematological malignancy and an invasive fungal infection.
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Notes |
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References |
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2 . Denning, D. W. (1998). Invasive aspergillosis. Clinical Infectious Diseases 26, 781805.[ISI][Medline]
3 . Walsh, T. J., Hiemenz, J. W., Seibel, N. L., Perfect, J. R., Horwith, G., Lee, L. et al. (1998). Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clinical Infectious Diseases 26, 138396.[ISI][Medline]
4 . Clevenbergh, P., Jacobs, F., Kentos, A., Byl, B., Collignon, L., Moerman, M. et al. (1998). Compassionate use of amphotericin B lipid complex (Abelcet) in life-threatening fungal infections: report of 30 cases. Clinical Microbiology and Infection 4, 1928.[Medline]
5 . Hiemenz, J. W. & Walsh, T. J. (1996). Lipid formulations of amphotericin B: recent progress and future directions. Clinical Infectious Diseases 22, Suppl. 2, S13344.[ISI][Medline]
6 . Adedoyin, A., Bernardo, J. F., Swenson, C. E., Bolsack, L. E., Horwith, G., DeWit, S. et al. (1997). Pharmacokinetic profile of ABELCET (Amphotericin B lipid complex injection): combined experience from phase I and phase II studies. Antimicrobial Agents and Chemotherapy 41, 22018.[Abstract]
7 . Linden, P. (1997). Efficacy of low-dose ABELCET (Amphotericin B lipid complex). In Abstracts of Focus on Fungal Infections 7, San Antonio, Texas, 1997. Abstract 268, p. 59.
8 . Sharkey, P. K., Graybill, J. R., Johnson, E. S., Hausrath, S. G., Pollard, R. B., Kolokathis, A. et al. (1996). Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS. Clinical Infectious Diseases 22, 31521.[ISI][Medline]
9 . Walsh, T. J., Whitcomb, P., Piscitelli, S., Figg, W. D., Hill, S., Chanock, S. J. et al.(1997). Safety, tolerance, and pharmacokinetics of amphotericin B lipid complex in children with hepatosplenic candidiasis. Antimicrobial Agents and Chemotherapy 41, 19448.[Abstract]
10
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Sundar, S., Agrawal, N. K., Sinha, P. R., Horwith, G. S.
& Murray, H. W. (1997). Short-course, low-dose amphotericin B lipid complex
therapy for visceral leishmaniasis unresponsive to antimony. Annals of Internal
Medicine 127, 1337.
Received 3 November 1998; returned 23 February 1999; revised 12 March 1999; accepted 23 May 1999