Amphotericin B lipid complex at 3 mg/kg/day for treatment of invasive fungal infections in adults with haematological malignancies

Rodrigo Martino*, Maricel Subirá, Anna Sureda and Jorge Sierra

Division of Clinical Haematology, Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni Ma Claret, 167, 08025 Barcelona, Spain


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
We treated 10 consecutive adults with a haematological malignancy, and an invasive aspergillosis (n = 8) or invasive candidosis (n = 2), with amphotericin B lipid complex (ABLC) at 3 mg/kg/day. Nine patients responded (five complete and four partial responses), and one died with invasive aspergillosis. Treatment was well tolerated, with only 4% of infusions followed by infusion-related adverse events, and the renal function improved in six patients who had an elevated serum creatinine before therapy. These data suggest that lower doses of ABLC may be equally effective but less toxic than higher doses. However, a controlled study is required to confirm these observations.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
Invasive fungal infections are an important cause of morbidity and mortality in patients with haematological malignancies. Although amphotericin B (AmB) is considered the treatment of choice for most invasive mycoses, its use is associated with serious adverse events in 40–60% of these patients, especially infusion-related reactions and nephrotoxicity.1 Several lipid formulations of AmB have been developed to reduce the toxicity and maximize the therapeutic utility of AmB. Amphotericin B lipid complex (ABLC) is one such formulation that has been approved in Europe and in the USA for treatment of invasive fungal infections in patients who are intolerant of or refractory to AmB deoxycholate or conventional AmB (c-AmB). The standard dosage of ABLC is 5 mg/kg/day, which is four to five times higher than the dosage recommended for c-AmB in treating aspergillosis. 2 ,3 ,4 Lower doses, however, may be equally effective and less toxic, although there have been few previous reports. Herein we report our experience with ABLC at 3 mg/kg/day in treating 10 adults with haematological malignancies and a proven high-risk invasive mycosis.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
From January 1997 to December 1998, 10 consecutive adults with a haematological malignancy and an invasive mycosis were studied. Patient details are shown in the Table. Most patients had an advanced acute leukaemia and three had undergone allogeneic bone marrow transplantation. Six patients were neutropenic at the start of ABLC treatment and received granulocyte-colony stimulating factor. The neutrophil count recovered in four patients in 5–22 days, while two patients did not recover neutrophils and died pancytopenic on days 11 and 32 of ABLC treatment.


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Table. Patient characteristics and treatment outcome
 
Six patients had an invasive pulmonary aspergillosis, two had isolated cutaneous aspergillosis, one had a chronic systemic candidosis and one had acute disseminated candidosis. The Table summarizes treatment outcome. Seven patients had a definite fungal infection as defined by isolation of Aspergillus spp. from broncho-alveolar lavage (BAL), a positive transbronchial biopsy in two cases of aspergillosis and post-mortem findings in one (case 8), and histological and microbiological evidence of the infection in the two cases of cutaneous aspergillosis. The patient with chronic candidosis had yeasts in the material obtained from a fine needle aspiration of a hepatic nodule, although fungal cultures were negative, and the patient with acute candidosis had Candida tropicalis fungaemia with septic shock, multiple cutaneous fungal lesions and bilateral pulmonary infiltrates. Three patients had a probable invasive pulmonary aspergillosis defined by isolation of Aspergillus spp. from BAL, but no attempt was made to obtain a confirmatory biopsy. All six patients with pulmonary aspergillosis and the patient with chronic systemic candidosis had clinical and radiological findings suggestive of the invasive mycosis, and no other pathogens were isolated from BAL or blood, except for patient 8, who was found to have cytomegalovirus pneumonitis and an Epstein–Barr virus-positive post-transplant lymphoproliferative disease at autopsy.

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.


    Results and discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
A total of 308 infusions of ABLC were given to the 10 patients, with a minimum of nine and a maximum of 104. Acute infusion-related adverse reactions occurred in 13 of these infusions (4%) in four patients, including fever, rigors and myalgias. These reactions occurred during the first infusions, were judged as mild by the treating physicians and resolved in later infusions. None of the patients developed nephrotoxicity, and in six patients who had an elevated serum creatinine at the start of therapy, the level decreased by the end of therapy (see Table). All patients required an increase in the parenteral potassium supplements by a median of 60 meq/day (range 30–100), and three had at least one serum potassium level of <3 meq/L. There were no other adverse reactions attributable to ABLC therapy.

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 0.6–2.5 mg/kg/day ABLC7 and a 62% (8/13) response for cryptococcal meningitis treated with 1.2–2.5 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 2–3 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.


    Notes
 
* Corresponding author. Tel: +34-934-919-396; Fax: +34-932-919-466; E-mail:rmartino{at}hsp.santpau.es Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
1 . Khoo, S. H., Bond, J. & Denning, D. W. (1994). Administering amphotericin B—A practical approach. Journal of Antimicrobial Chemotherapy 33, 201–13.

2 . Denning, D. W. (1998). Invasive aspergillosis. Clinical Infectious Diseases 26, 781–805.[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, 1383–96.[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, 192–8.[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, S133–44.[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, 2201–8.[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, 315–21.[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, 1944–8.[Abstract]

10 . 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, 133–7.[Abstract/Free Full Text]

Received 3 November 1998; returned 23 February 1999; revised 12 March 1999; accepted 23 May 1999





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