Liposomal Amphotericin B
- 128 Downloads
Incorporation of amphotericin B into small unilamellar liposomes (AmBisome® ) alters the pharmacokinetic properties of the drug, but allows it to retain significant in vitro and in vivo tactivity against fungal species, including Candida, Aspergillus and Cryptococcus, and parasites of the genus Leishmania.
Used as prophylaxis against fungal infections in immunocompromised patients, liposomal amphotericin B appeared to reduce the incidence of both fungal colonisation and proven fungal infections, but did not affect overall survival.
Empirical therapy with liposomal amphotericin B in immunocompromised adults or children with suspected fungal infections was at least as effective as therapy with conventional amphotericin B. In the largest noncomparative studies, liposomal amphotericin B produced mycological eradication in 40 and 83% of patients with proven Candida infections and 41 and 60% with proven Aspergillus infections; however, these studies included relatively few patients. Mycological eradication rates of 67 to 85% in patients with cryptococcal meningitis have been reported
Liposomal amphotericin B is an effective treatment for visceral leishmaniasis in immunocompetent adults and children, including those with severe or drug-resistant disease. The drug also produces good response rates in immunocompromised patients; however, relapse rates in these patients are high.
Liposomal amphotericin B is generally well tolerated. Few patients require discontinuation or dose reduction of the drug because of adverse events. The most frequently reported adverse events are hypokalaemia, nephrotoxicity and infusion-related reactions; however, these occur significantly less often after liposomal amphotericin B than after the conventional formulation of the drug.
The acquisition cost of liposomal amphotericin B is higher than that of conventional amphotericin B. Cost-effectiveness analyses did not clearly show an economic benefit for empirical liposomal amphotericin B antifungal therapy in adults; however, one model suggested that initial empirical therapy with the liposomal formulation in children may cost less per cure than initial therapy with the conventional formulation.
Liposomal amphotericin B appears to be an effective alternative to conventional amphotericin B in the management of immunocompromised patients with proven or suspected fungal infections. Use of the drug is facilitated by its greatly improved tolerability profile compared with conventional amphotericin B. Because of this, liposomal amphotericin should be preferred to conventional amphotericin B in the management of suspected or proven fungal infections in immunocompromised patients with pre-existing renal dysfunction, amphotericin B-induced toxicity or failure to respond to conventional amphotericin B. Liposomal amphotericin B may also be considered for first- or second-line treatment of immunocompetent patients with visceral leishmaniasis.
Amphotericin B is a macrocyclic polyene antibiotic which acts via inhibition of membrane function in susceptible fungal and Leishmania cells. Liposomal amphotericin B (AmBisome®) — produced by incorporation of amphotericin B into small, unilamellar liposomes — accumulates at sites of fungal infection, binding directly to fungal cells and causing cell death. Drug and liposome remain closely associated in circulation, permitting the administration of higher doses with reduced toxicity relative to conventional amphotericin B.
Liposomal amphotericin B is active in vitro and in vivo against a variety of pathogenic fungi and Leishmania species. In rodent models of Candida, Aspergillus and Cryptococcus infection, liposomal amphotericin B was administered in higher doses than the conventional drug, generally producing greater reductions in fungal burden. Survival rates were generally similar between the 2 formulations, although liposomal amphotericin B improved cure rates and survival compared with lower doses of conventional amphotericin B in some studies. When the 2 formulations were administered in identical milligram per kilogram dosages, they had similar effects on survival in infected animals, and conventional amphotericin B tended to produce a greater reduction in fungal burden. Against murine visceral leishmaniasis, liposomal amphotericin B was considerably more effective than conventional amphotericin B or meglumine antimonate, and it produced clinical improvement with significantly fewer doses than the latter agent.
After intravenous administration, liposomal amphotericin B achieves a higher peak serum concentration and larger area under the serum concentration-time curve than conventional amphotericin B. The drug appears to be taken up extensively by the reticuloendothelial system. High concentrations of drug are detected in liver and spleen, with lower concentrations found in brain, CSF, bone marrow, heart and lung.
The apparent mean half-life of liposomal amphotericin B is approximately 6 to 7 hours. Elimination of liposomal amphotericin B, like that of the conventional formulation, is poorly understood. No metabolites are known.
Therapeutic Use in Fungal Infections
Liposomal amphotericin B fungal prophylaxis was more effective than placebo in immunocompromised patients. The drug significantly reduced rates of invasive fungal infection in liver transplant recipients; among bone marrow transplant recipients, liposomal amphotericin B reduced the rate of fungal colonisation, but not invasive fungal infection. Overall survival was not affected.
Empirical therapy with liposomal amphotericin B in immunocompromised adults and children with suspected fungal infections was at least as effective as therapy with conventional amphotericin B in randomised studies. Evidence from noncomparative studies confirms the effectiveness of empirical liposomal amphotericin B in patients with suspected fungal infections, including patients who had experienced prior inefficacy or toxicity with conventional amphotericin B.
Limited data from noncomparative studies suggest that liposomal amphotericin B is effective against invasive Candida and Aspergillus infection and oral candidosis. However, fewer than 20 patients with each infection were evaluable in most studies. In the largest available studies, liposomal amphotericin B produced mycological eradication in 41 and 60% of patients with Aspergillus infection and 40 and 83% of patients infected by Candida spp. 67 to 85% of patients with AIDS and cryptococcal infection (primarily meningitis) who received liposomal amphotericin B achieved mycological eradication.
Therapeutic Use in Visceral Leishmaniasis
Liposomal amphotericin B is an effective treatment for visceral leishmaniasis (kala azar) in immunocompetent adults and children, clearing parasites in 100% of patients in several studies. The drug is also effective in patients with severe or pentavalent antimonial-resistant disease; however, response rates appear to be lower. In most immunocompetent patients, symptomatic improvement and objective response are detectable within 1 week of starting therapy. Liposomal amphotericin B also produces good response rates in immunocompromised patients; however, relapse rates are high. No comparative data are available.
Liposomal amphotericin B was generally well tolerated. The drug was discontinued because of adverse events in <5% of patients. Liposomal amphotericin B recipients experienced fewer adverse events than patients who received conventional amphotericin B. The most frequently reported adverse events in the liposomal amphotericin B group included hypokalaemia, nephrotoxicity and infusion-related fever and rigors. Increased serum liver enzymes have been noted in a substantial proportion of liposomal amphotericin B recipients. However, these patients may have been predisposed to elevations in liver enzymes by concomitant drugs or disease states; causality is unclear.
Dosage and Administration
Liposomal amphotericin B is administered as a single daily dose by slow intravenous infusion. Premedication is not required.
Used for empirical antifungal therapy in immunocompromised patients, the recommended (US) liposomal amphotericin B dosage is 3 mg/kg/day. Patients with proven systemic fungal infections should receive 3 to 5 mg/kg/day (US) or 1 to 3 mg/kg/day (UK). The optimum duration of antifungal therapy is not well defined. In neutropenic patients, treatment is generally continued until the recovery of neutrophil counts. A dosage of liposomal amphotericin B 1 mg/kg/day has been used for fungal prophylaxis after bone marrow or liver transplantation.
In immunocompetent patients with visceral leishmaniasis, liposomal amphotericin B 3 mg/kg should be administered on days 1 to 5, 14 and 21. In immunocompromised patients, the recommended dosage is 3 mg/kg/day on days 1 to 5 and 4 mg/kg/day on days 10, 17, 24, 31 and 38. Other regimens of 21 to 30 mg/kg administered over 10 to 21 days may also be appropriate. as]Pharmacoeconomic Implications of Liposomal Amphotericin B
The acquisition cost of liposomal amphotericin B is considerably higher than that of the conventional formulation. Because of this, the prophylactic use of liposomal amphotericin B may be difficult to justify. One cost-effectiveness analysis of empirical liposomal amphotericin B therapy suggested that savings associated with the reduced toxicity and improved efficacy of the liposomal formulation in immunocompromised adults with proven or suspected fungal infections were not enough to offset its increased acquisition cost compared with the conventional formulation. Another model suggested that initial empirical therapy with liposomal amphotericin B may cost less per complete cure than the conventional formulation in children, but not in adults. No pharmacoeconomic data are available for the use of liposomal amphotericin B in patients with visceral leishmaniasis.
KeywordsAdis International Limited Visceral Leishmaniasis Liposomal Amphotericin Liposomal Formulation Cryptococcal Meningitis
Unable to display preview. Download preview PDF.
- 1.Richardson MD, Warnock DW. Fungal Infection: diagnosis and management. Oxford: Blackwell Scientific Publications, 1993Google Scholar
- 6.Pallister CJ, Johnson EM, Warnock DW, et al. In-vitro effects of liposome-encapsulated amphotericin B (AmBisome) and amphotericin B-deoxycholate (Fungizone) on the phagocytic and candidacidal function of human polymorphonuclear leucocytes. J Antimicrob Chemother 1992 Sep; 30: 313–20PubMedCrossRefGoogle Scholar
- 13.van Etten EW, van den Heuvel-de-Groot C, Bakker-Woudenberg IA. Efficacies of amphotericin B-desoxycholate (Fungizone), liposomal amphotericin B (AmBisome) and fluconazole in the treatment of systemic candidosis in immunocompetent and leucopenic mice. J Antimicrob Chemother 1993 Nov; 32: 723–39PubMedCrossRefGoogle Scholar
- 14.Kretschmar M, Nichterlein T, Hof H. Ambisome is superior to amphotericin B in lipid suspensions for treatment of murine candidiasis [abstract]. 7th Eur Congr Clin Microbiol Infect Dis 1995: 155Google Scholar
- 16.Francis P, Lee JW, Hoffman A, et al. Efficacy of unilamellar liposomal amphotericin B in treatment of pulmonary aspergillosis in persistently granulocytopenic rabbits: the potential role of bronchoalveolar D-mannitol and serum galactomannan as markers of infection. J Infect Dis 1994 Feb; 169: 356–68PubMedCrossRefGoogle Scholar
- 18.Vassiloyanakopoulos A, Boutsikakis J, Mylonakis EE, et al. Comparative therapeutic efficacy of two amphotericin B liposomal forms in aspergillus fumigatus (AF) experimental endocarditis [abstract]. Clin Infect Dis 1995 Sep; 21: 779Google Scholar
- 19.Albert MM, Stahl-Carroll TL, Luther MF, et al. Comparison of liposomal amphotericin B to amphotericin B for treatment of murine cryptococcal meningitis. J Mycol Med 1995; 5(1): 1–6Google Scholar
- 33.Walsh TJ, Bekersky I, Yeldandi V, et al. Pharmacokinetics of AmBisome in persistently febrile neutropenic patients receiving empirical antifungal therapy [abstract no. A13]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): 1995 Sep 17–20; 3Google Scholar
- 34.NeXstar Pharmaceuticals Inc. AmBisome(R) (amphotericin B) lipossome for injection: prescribing information. Deerfield, IL, USA, Aug 1997Google Scholar
- 36.Tollemar J, Ringden O, Tyden G. Liposomal amphotericin-B (Ambisome) treatment in solid organ and bone marrow transplant recipients. Efficacy and safety evaluation. Clin Transpl 1990 Jun; 4: 167–75Google Scholar
- 38.Gonzalez C, Sein T, Bacher J, et al. Penetration of lipid formulations of amphotericin B into cerbrospinal fluid and brain tissue [abstract no. A-90]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): 1997 Sep 28–Oct 1; Toronto, 19Google Scholar
- 44.Walsh T, Bodensteiner D, Hiemenz J, et al. A randomized, double-blind trial of AmBisome (liposomal amphotericin B) versus amphotericin B in the empirical treatment of persistently febrile neutropenic patients [abstract no. LM-90]. 37th Inter-science Conference on Antimicrobial Agents and Chemotherapy (ICAAC): 1997 Sep 28–Oct 1; Toronto, 381Google Scholar
- 48.Heinemann V, Pyka S, Bosse D, et al. Liposomal amphotericin B (AmBisome): clinical safety and efficacy [abstract]. Onkologie 1995 Oct; 18 Suppl. 2: 198Google Scholar
- 51.Nowoczyn V, Ritter J, Boos J, et al. Liposomal amphotericin B (ambisome) in neutropenic children with hematological malignancies and systemic fungal infections [abstract]. Med Pediatr Oncol 1992; 20(5): 376Google Scholar
- 53.Leenders ACAP, Daenen S, Jansen RLH, et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B in the treatment of neutropenia-associated invasive fungal infections [abstract]. Trends in Invasive Fungal Infections 4: 1997 Nov 5; BarcelonaGoogle Scholar
- 55.Ellis M, Spence D, Meunier F, et al. Randomised multicentre trial of 1 mg/kg (LD) versus 4 mg/kg (HD) liposomal amphotericin B (AmBisome) (LAB) in the treatment of invasive aspergillosis (IA): EORTC protocol 19923 [abstract no. LM39]. 36th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), American Society for Microbiology: 1996 Sep 15–19; New OrleansGoogle Scholar
- 56.Devecioglu Ö, Özgen Ü, Agaoglu L, et al. Clinical experience with amphotericin B (conventional & liposomal) in febrile neutropenic children [abstract]. Can J Infect Dis 1995 Jul; 6 Suppl. C 365CGoogle Scholar
- 57.Dornbusch HJ, Urban CE, Pinter H, et al. Treatment of invasive pulmonary aspergillosis in severely neutropenic children with malignant disorders using liposomal amphotericin B (AmBisome), granulocyte colony-stimulating factor, and surgery: report of five cases. Pediatr Hematol Oncol 1995 Nov–Dec; 12: 577–86PubMedCrossRefGoogle Scholar
- 60.Lazar JT, Ksionski GE. Efficacy of safety of AmBisome (liposomal amphotericin B) in primary episodes of cryptococcosis in patients with HIV infection [abstract no. W.B.2177]. 7th International Conference on AIDS: 1991 Jun 16–21; NGoogle Scholar
- 61.Mota-Miranda A, Gomes H, Marques R, et al. Liposomal amphotericin B in the treatment of opportunistic fungal infections. Rev Esp Quimioter 1994 Jun; 7: 146–9Google Scholar
- 63.Codeluppi M, Mussini C, Borghi V, et al. Liposomal amphotericin B in therapy in patients with AIDS [abstract no. P34]. Glasgow AIDS Meeting 1992 NovGoogle Scholar
- 67.Fisher NC, Mutimer DJ. Targeted and empirical liposomal amphotericin B therapy in liver transplantation: a 2-year review [abstract no. 1537]. Hepatology 1996; 24 (4, Pt. 2) Program Suppl.: 511AGoogle Scholar
- 91.NeXstar Pharmaceuticals Limited. AmBisome: summary of product characteristics. Cambridge, England. 1996 Feb 07Google Scholar
- 92.NeXstar Pharmaceuticals Inc. Ambisome(R) (liposomal amphotericin B.P.): product monograph. Boulder, Colorado, USA, 1995Google Scholar
- 93.Pereira da Silva L, Videira Amaral JM, Cordeiro Ferreira N. Which is the most appropriate dosage of liposomal Amphotericin-B (AmBisome) for the treatment of fungal infections in infants of very low birth weight? [letter; comment]. Pediatrics 1993 Jun; 91: 1217–8Google Scholar
- 95.Leibovitz E, Juster A, Amitay A, et al. Liposomal amphotericin B (AmBisome) in the treatment of disseminated fungal infections in very low birth weight (VLBW) infants [abstract no. 4112]. 20th International Congress of Chemotherapy: 1997 Jun 29–Jul 3; Sydney, 128Google Scholar
- 96.Drugs used in the treatment of infection. British National Formulary. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain, 1997 Sep: 230–292Google Scholar
- 99.Boogaerts M, Tormans G, Maes E, et al. Cost-effectiveness analysis of Ambisome (AMB) vs amphotericin B (AMPHOB) in the empiric treatment of febrile neutropenia in adults and children [abstract no. 55-IV]. Blood 1996 Nov 15; 88 Suppl. 1: 501aGoogle Scholar
- 101.Richardson MD. Systemic fungal infections . Care Critically Ill 1994; 10: 258–61Google Scholar
- 107.Mahgoub ES. Agents of mycetoma. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious disease. 4th ed. ed. Vol. 2. New York: Churchill Livingstone, 1995: 2327–40Google Scholar
- 110.British Society for Antimicrobial Chemotherapy Working Party. Antifungal chemotherapy in patients with acquired immunodeficiency syndrome. Lancet 1992; 340: 648–51Google Scholar
- 113.Pearson RD, de Queiroz Sousa A. Leishmania species: visceral (kala-azar), cutaneous, and mucosal leishmaniasis. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious disease. 4th ed. ed. Vol. 2. New York: Churchill Livingstone, 1995: 2428–42Google Scholar