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Liposomal Amphotericin B (AmBisome®): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future Directions

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Abstract

Liposomal amphotericin B (AmBisome®; LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. LAmB has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients.

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References

  1. Wingard JR, White MH, Anaissie E, Raffalli J, Goodman J, Arrieta A, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin Infect Dis. 2000;31(5):1155–63.

    Article  CAS  PubMed  Google Scholar 

  2. Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol. 1965;13(1):238–52.

    Article  CAS  PubMed  Google Scholar 

  3. Adler-Moore JP, Proffitt PR. Development, characterization, efficacy and mode of action of ambisome,’ a unilamellar liposomal formulation of amphotericin b. J Liposome Res;1993;3(3);429–50.

  4. Papahadjopoulos D, Jacobson K, Nir S, Isac T. Phase transitions in phospholipid vesicles. Fluorescence polarization and permeability measurements concerning the effect of temperature and cholesterol. Biochim Biophys Acta. 1973;311(3):330–48.

    Article  CAS  PubMed  Google Scholar 

  5. Fujii G, Chang JE, Coley T, Steere B. The formation of amphotericin B ion channels in lipid bilayers. Biochemistry. 1997;36(16):4959–68.

    Article  CAS  PubMed  Google Scholar 

  6. Adler-Moore J, Proffitt RT. Am Bisome: liposomal formulation, structure, mechanism of action and pre-clinical experience. J Antimicrob Chemother. 2002;49(Suppl 1):21–30.

    Article  CAS  PubMed  Google Scholar 

  7. Wasan EK, Gershkovich P, Zhao J, Zhu X, Werbovetz K, Tidwell RR, et al. A novel tropically stable oral amphotericin B formulation (iCo-010) exhibits efficacy against visceral Leishmaniasis in a murine model. PLoS Negl Trop Dis. 2010;4(12):e913.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013;73(9):919–34.

    Article  CAS  PubMed  Google Scholar 

  9. Adler-Moore JP, Proffitt RT. Amphotericin B lipid preparations: what are the differences? Clin Microbiol Infect. 2008;14(Suppl 4):25–36.

    Article  CAS  PubMed  Google Scholar 

  10. Adler-Moore J. Am Bisome targeting to fungal infections. Bone Marrow Transplant. 1994;14(Suppl 5):S3–7.

    PubMed  Google Scholar 

  11. Lestner JM, Howard SJ, Goodwin J, Gregson L, Majithiya J, Walsh TJ, et al. Pharmacokinetics and pharmacodynamics of amphotericin B deoxycholate, liposomal amphotericin B, and amphotericin B lipid complex in an in vitro model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2010;54(8):3432–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Takemoto K, Yamamoto Y, Ueda Y. Evaluation of antifungal pharmacodynamic characteristics of Am Bisome against Candida albicans. Microbiol Immunol. 2006;50(8):579–86.

    Article  CAS  PubMed  Google Scholar 

  13. Readio JD, Bittman R. Equilibrium binding of amphotericin B and its methyl ester and borate complex to sterols. Biochim Biophys Acta. 1982;685(2):219–24.

    Article  CAS  PubMed  Google Scholar 

  14. Shimizu K, Osada M, Takemoto K, Yamamoto Y, Asai T, Oku N. Temperature-dependent transfer of amphotericin B from liposomal membrane of Am Bisome to fungal cell membrane. J Control Release. 2010;141(2):208–15.

    Article  CAS  PubMed  Google Scholar 

  15. Mouton JW, Theuretzbacher U, Craig WA, Tulkens PM, Derendorf H, Cars O. Tissue concentrations: do we ever learn? J Antimicrob Chemother. 2008;61(2):235–7.

    Article  CAS  PubMed  Google Scholar 

  16. Garcia A, Adler-Moore JP, Proffitt RT. Single-dose Am Bisome (Liposomal amphotericin B) as prophylaxis for murine systemic candidiasis and histoplasmosis. Antimicrob Agents Chemother. 2000;44(9):2327–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Olson JA, Adler-Moore JP, Schwartz J, Jensen GM, Proffitt RT. Comparative efficacies, toxicities, and tissue concentrations of amphotericin B lipid formulations in a murine pulmonary aspergillosis model. Antimicrob Agents Chemother. 2006;50(6):2122–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Boswell GW, Bekersky I, Buell D, Hiles R, Walsh TJ. Toxicological profile and pharmacokinetics of a unilamellar liposomal vesicle formulation of amphotericin B in rats. Antimicrob Agents Chemother. 1998;42(2):263–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. van Etten EW, ten Kate MT, Stearne LE, Bakker-Woudenberg IA. Amphotericin B liposomes with prolonged circulation in blood: in vitro antifungal activity, toxicity, and efficacy in systemic candidiasis in leukopenic mice. Antimicrob Agents Chemother. 1995;39(9):1954–8.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Smith PJ, Olson JA, Constable D, Schwartz J, Proffitt RT, Adler-Moore JP. Effects of dosing regimen on accumulation, retention and prophylactic efficacy of liposomal amphotericin B. J Antimicrob Chemother. 2007;59(5):941–51.

    Article  CAS  PubMed  Google Scholar 

  21. Bekersky I, Boswell GW, Hiles R, Fielding RM, Buell D, Walsh TJ. Safety, toxicokinetics and tissue distribution of long-term intravenous liposomal amphotericin B (AmBisome): a 91-day study in rats. Pharm Res. 2000;17(12):1494–502.

    Article  CAS  PubMed  Google Scholar 

  22. Lee JW, Amantea MA, Francis PA, Navarro EE, Bacher J, Pizzo PA, et al. Pharmacokinetics and safety of a unilamellar liposomal formulation of amphotericin B (AmBisome) in rabbits. Antimicrob Agents Chemother. 1994;38(4):713–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bekersky I, Boswell GW, Hiles R, Fielding RM, Buell D, Walsh TJ. Safety and toxicokinetics of intravenous liposomal amphotericin B (AmBisome) in beagle dogs. Pharm Res. 1999;16(11):1694–701.

    Article  CAS  PubMed  Google Scholar 

  24. Gregoriadis G. Overview of liposomes. J Antimicrob Chemother. 1991;28(Suppl B):39–48.

  25. Gershkovich P, Wasan EK, Lin M, Sivak O, Leon CG, Clement JG, et al. Pharmacokinetics and biodistribution of amphotericin B in rats following oral administration in a novel lipid-based formulation. J Antimicrob Chemother. 2009;64(1):101–8.

    Article  CAS  PubMed  Google Scholar 

  26. Groll AH, Giri N, Petraitis V, Petraitiene R, Candelario M, Bacher JS, et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis. 2000;182(1):274–82.

    Article  CAS  PubMed  Google Scholar 

  27. Groll AH, Lyman CA, Petraitis V, Petraitiene R, Armstrong D, Mickiene D, et al. Compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations. Antimicrob Agents Chemother. 2006;50(10):3418–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother. 2002;46(3):828–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Würthwein G, Young C, Lanvers-Kaminsky C, Hempel G, Trame MN, Schwerdtfeger R, et al. Population pharmacokinetics of liposomal amphotericin B and caspofungin in allogeneic hematopoietic stem cell recipients. Antimicrob Agents Chemother. 2012;56(1):536–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Hong Y, Shaw PJ, Nath CE, Yadav SP, Stephen KR, Earl JW, et al. Population pharmacokinetics of liposomal amphotericin B in pediatric patients with malignant diseases. Antimicrob Agents Chemother. 2006;50(3):935–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hope WW, Goodwin J, Felton TW, Ellis M, Stevens DA. Population pharmacokinetics of conventional and intermittent dosing of liposomal amphotericin B in adults: a first critical step for rational design of innovative regimens. Antimicrob Agents Chemother. 2012;56(10):5303–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate. Antimicrob Agents Chemother. 2002;46(3):834–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Walsh TJ, Yeldandi V, McEvoy M, Gonzalez C, Chanock S, Freifeld A, et al. Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients. Antimicrob Agents Chemother. 1998;42(9):2391–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Moriyama B, Torabi-Parizi P, Pratt AK, Henning SA, Pennick G, Shea YR, et al. Pharmacokinetics of liposomal amphotericin B in pleural fluid. Antimicrob Agents Chemother. 2010;54(4):1633–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vogelsinger H, Weiler S, Djanani A, Kountchev J, Bellmann-Weiler R, Wiedermann CJ, et al. Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion. J Antimicrob Chemother. 2006;57(6):1153–60.

    Article  CAS  PubMed  Google Scholar 

  36. Strenger V, Meinitzer A, Donnerer J, Hofer N, Dornbusch HJ, Wanz U, et al. Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B. J Antimicrob Chemother. 2014;69(9):2522–6.

    Article  CAS  PubMed  Google Scholar 

  37. Heinemann V, Bosse D, Jehn U, Kähny B, Wachholz K, Debus A, et al. Pharmacokinetics of liposomal amphotericin B (Ambisome) in critically ill patients. Antimicrob Agents Chemother. 1997;41(6):1275–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Wurtz R, Itokazu G, Rodvold K. Antimicrobial dosing in obese patients. Clin Infect Dis. 1997;25(1):112–8.

    Article  CAS  PubMed  Google Scholar 

  39. Polso AK, Lassiter JL, Nagel JL. Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review. J Clin Pharm Ther. 2014;39(6):584–608.

    Article  CAS  PubMed  Google Scholar 

  40. Nath CE, McLachlan AJ, Shaw PJ, Coakley JC, Earl JW. Amphotericin B dose optimization in children with malignant diseases. Chemotherapy. 2007;53(2):142–7.

    Article  CAS  PubMed  Google Scholar 

  41. Pagliano P, Carannante N, Rossi M, Gramiccia M, Gradoni L, Faella FS, et al. Visceral leishmaniasis in pregnancy: a case series and a systematic review of the literature. J Antimicrob Chemother. 2005;55(2):229–33.

    Article  CAS  PubMed  Google Scholar 

  42. Takemoto K, Yamamoto Y, Ueda Y, Sumita Y, Yoshida K, Niki Y. Comparative study on the efficacy of Am Bisome and Fungizone in a mouse model of pulmonary aspergillosis. J Antimicrob Chemother. 2006;57(4):724–31.

    Article  CAS  PubMed  Google Scholar 

  43. Al-Nakeeb Z, Petraitis V, Goodwin J, Petraitiene R, Walsh TJ, Hope WW. Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus. Antimicrob Agents Chemother. 2015;59(5):2735–45.

  44. Clemons KV, Schwartz JA, Stevens DA. Experimental central nervous system aspergillosis therapy: efficacy, drug levels and localization, immunohistopathology, and toxicity. Antimicrob Agents Chemother. 2012;56(8):4439–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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;32(5):723–39.

    Article  CAS  PubMed  Google Scholar 

  46. Olson JA, Adler-Moore JP, Smith PJ, Proffitt RT. Treatment of Candida glabrata infection in immunosuppressed mice by using a combination of liposomal amphotericin B with caspofungin or micafungin. Antimicrob Agents Chemother. 2005;49(12):4895–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Clemons KV, Stevens DA. Therapeutic efficacy of a liposomal formulation of amphotericin B (AmBisome) against murine blastomycosis. J Antimicrob Chemother. 1993;32(3):465–72.

    Article  CAS  PubMed  Google Scholar 

  48. Ibrahim AS, Gebremariam T, Husseiny MI, Stevens DA, Fu Y, Edwards JE, et al. Comparison of lipid amphotericin B preparations in treating murine zygomycosis. Antimicrob Agents Chemother. 2008;52(4):1573–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Graybill JR, Bocanegra R. Liposomal amphotericin B therapy of murine histoplasmosis. Antimicrob Agents Chemother. 1995;39(8):1885–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. O’Connor L, Livermore J, Sharp AD, Goodwin J, Gregson L, Howard SJ, et al. Pharmacodynamics of liposomal amphotericin B and flucytosine for cryptococcal meningoencephalitis: safe and effective regimens for immunocompromised patients. J Infect Dis. 2013;208(2):351–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Mistro S, Maciel IeM, de Menezes RG, Maia ZP, Schooley RT, Badaró R. Does lipid emulsion reduce amphotericin B nephrotoxicity? A systematic review and meta-analysis. Clin Infect Dis. 2012;54(12):1774–7.

    Article  CAS  PubMed  Google Scholar 

  52. Wasan KM, Morton RE, Rosenblum MG, Lopez-Berestein G. Decreased toxicity of liposomal amphotericin B due to association of amphotericin B with high-density lipoproteins: role of lipid transfer protein. J Pharm Sci. 1994;83(7):1006–10.

    Article  CAS  PubMed  Google Scholar 

  53. Loo AS, Muhsin SA, Walsh TJ. Toxicokinetic and mechanistic basis for the safety and tolerability of liposomal amphotericin B. Expert Opin Drug Saf. 2013;12(6):881–95.

    Article  CAS  PubMed  Google Scholar 

  54. Sau K, Mambula SS, Latz E, Henneke P, Golenbock DT, Levitz SM. The antifungal drug amphotericin B promotes inflammatory cytokine release by a Toll-like receptor- and CD14-dependent mechanism. J Biol Chem. 2003;278(39):37561–8.

    Article  CAS  PubMed  Google Scholar 

  55. Roden MM, Nelson LD, Knudsen TA, Jarosinski PF, Starling JM, Shiflett SE, et al. Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics. Clin Infect Dis. 2003;36(10):1213–20.

    Article  CAS  PubMed  Google Scholar 

  56. Szebeni J, Baranyi L, Savay S, Bodo M, Morse DS, Basta M, et al. Liposome-induced pulmonary hypertension: properties and mechanism of a complement-mediated pseudoallergic reaction. Am J Physiol Heart Circ Physiol. 2000;279(3):H1319–28.

    CAS  PubMed  Google Scholar 

  57. Wade RL, Chaudhari P, Natoli JL, Taylor RJ, Nathanson BH, Horn DL. Nephrotoxicity and other adverse events among inpatients receiving liposomal amphotericin B or amphotericin B lipid complex. Diagn Microbiol Infect Dis. 2013;76(3):361–7.

    Article  CAS  PubMed  Google Scholar 

  58. Patel GP, Crank CW, Leikin JB. An evaluation of hepatotoxicity and nephrotoxicity of liposomal amphotericin B (L-AMB). J Med Toxicol. 2011;7(1):12–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fischer MA, Winkelmayer WC, Rubin RH, Avorn J. The hepatotoxicity of antifungal medications in bone marrow transplant recipients. Clin Infect Dis. 2005;41(3):301–7.

    Article  CAS  PubMed  Google Scholar 

  60. Kolve H, Ahlke E, Fegeler W, Ritter J, Jürgens H, Groll AH. Safety, tolerance and outcome of treatment with liposomal amphotericin B in paediatric patients with cancer or undergoing haematopoietic stem cell transplantation. J Antimicrob Chemother. 2009;64(2):383–7.

    Article  CAS  PubMed  Google Scholar 

  61. Chamilos G, Luna M, Lewis RE, Chemaly R, Raad II, Kontoyiannis DP. Effects of liposomal amphotericin B versus an amphotericin B lipid complex on liver histopathology in patients with hematologic malignancies and invasive fungal infections: a retrospective, nonrandomized autopsy study. Clin Ther. 2007;29(9):1980–6.

    Article  CAS  PubMed  Google Scholar 

  62. Astellas Pharma US, AmBisome® package insert. Document Number 2C019-AMB-WPI. March 2012.

  63. Lewis RE, Albert ND, Kontoyiannis DP. Efficacy of single-dose liposomal amphotericin B or micafungin prophylaxis in a neutropenic murine model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2008;52(11):4178–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Penack O, Schwartz S, Martus P, Reinwald M, Schmidt-Hieber M, Thiel E, et al. Low-dose liposomal amphotericin B in the prevention of invasive fungal infections in patients with prolonged neutropenia: results from a randomized, single-center trial. Ann Oncol. 2006;17(8):1306–12.

    Article  CAS  PubMed  Google Scholar 

  65. Uhlenbrock S, Zimmermann M, Fegeler W, Jürgens H, Ritter J. Liposomal amphotericin B for prophylaxis of invasive fungal infections in high-risk paediatric patients with chemotherapy-related neutropenia: interim analysis of a prospective study. Mycoses. 2001;44(11–12):455–63.

    Article  CAS  PubMed  Google Scholar 

  66. Singh N, Paterson DL, Gayowski T, Wagener MM, Marino IR. Preemptive prophylaxis with a lipid preparation of amphotericin B for invasive fungal infections in liver transplant recipients requiring renal replacement therapy. Transplantation. 2001;71(7):910–3.

    Article  CAS  PubMed  Google Scholar 

  67. Shah T, Lai WK, Gow P, Leeming J, Mutimer D. Low-dose amphotericin for prevention of serious fungal infection following liver transplantation. Transpl Infect Dis. 2005;7(3–4):126–32.

  68. Fortun J, Martin-Davila P, Moreno S, Barcena R, de Vicente E, Honrubia A, et al. Prevention of invasive fungal infections in liver transplant recipients: the role of prophylaxis with lipid formulations of amphotericin B in high-risk patients. J Antimicrob Chemother. 2003;52(5):813–9.

    Article  CAS  PubMed  Google Scholar 

  69. Prentice HG, Hann IM, Herbrecht R, Aoun M, Kvaloy S, Catovsky D, et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol. 1997;98(3):711–8.

    Article  CAS  PubMed  Google Scholar 

  70. Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999;340(10):764–71.

    Article  CAS  PubMed  Google Scholar 

  71. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351(14):1391–402.

    Article  CAS  PubMed  Google Scholar 

  72. Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346(4):225–34.

    Article  CAS  PubMed  Google Scholar 

  73. Francis P, Lee JW, Hoffman A, Peter J, Francesconi A, Bacher J, 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;169(2):356–68.

    Article  CAS  PubMed  Google Scholar 

  74. Kirkpatrick WR, Coco BJ, Patterson TF. Sequential or combination antifungal therapy with voriconazole and liposomal amphotericin B in a Guinea pig model of invasive aspergillosis. Antimicrob Agents Chemother. 2006;50(4):1567–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Olson JA, George A, Constable D, Smith P, Proffitt RT, Adler-Moore JP. Liposomal amphotericin B and echinocandins as monotherapy or sequential or concomitant therapy in murine disseminated and pulmonary Aspergillus fumigatus infections. Antimicrob Agents Chemother. 2010;54(9):3884–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Leenders AC, Daenen S, Jansen RL, Hop WC, Lowenberg B, Wijermans PW, et al. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections. Br J Haematol. 1998;103(1):205–12.

    Article  CAS  PubMed  Google Scholar 

  77. Krüger W, Stockschläder M, Sobottka I, Betker R, De Wit M, Kröger N, et al. Antimycotic therapy with liposomal amphotericin-B for patients undergoing bone marrow or peripheral blood stem cell transplantation. Leuk Lymphoma. 1997;24(5–6):491–9.

    Article  PubMed  Google Scholar 

  78. Ellis M, Spence D, de Pauw B, Meunier F, Marinus A, Collette L, et al. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages of liposomal amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis. 1998;27(6):1406–12.

    Article  CAS  PubMed  Google Scholar 

  79. Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ, Bouza E, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44(10):1289–97.

    Article  CAS  PubMed  Google Scholar 

  80. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327–60.

    Article  CAS  PubMed  Google Scholar 

  81. Adler-Moore JP, Chiang SM, Satorius A, Guerra D, McAndrews B, McManus EJ, et al. Treatment of murine candidosis and cryptococcosis with a unilamellar liposomal amphotericin B formulation (AmBisome). J Antimicrob Chemother. 1991;28(Suppl B):63–71.

  82. Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet. 2007;369(9572):1519–27.

    Article  CAS  PubMed  Google Scholar 

  83. Queiroz-Telles F, Berezin E, Leverger G, Freire A, van der Vyver A, Chotpitayasunondh T, et al. Micafungin versus liposomal amphotericin B for pediatric patients with invasive candidiasis: substudy of a randomized double-blind trial. Pediatr Infect Dis J. 2008;27(9):820–6.

    Article  PubMed  Google Scholar 

  84. Day JN, Chau TT, Lalloo DG. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368(26):2522–3.

    Article  CAS  PubMed  Google Scholar 

  85. Sun HY, Alexander BD, Lortholary O, Dromer F, Forrest GN, Lyon GM, et al. Lipid formulations of amphotericin B significantly improve outcome in solid organ transplant recipients with central nervous system cryptococcosis. Clin Infect Dis. 2009;49(11):1721–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hamill RJ, Sobel JD, El-Sadr W, Johnson PC, Graybill JR, Javaly K, et al. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety. Clin Infect Dis. 2010;51(2):225–32.

    Article  CAS  PubMed  Google Scholar 

  87. Leenders AC, Reiss P, Portegies P, Clezy K, Hop WC, Hoy J, et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS. 1997;11(12):1463–71.

    Article  CAS  PubMed  Google Scholar 

  88. Coker RJ, Viviani M, Gazzard BG, Du Pont B, Pohle HD, Murphy SM, et al. Treatment of cryptococcosis with liposomal amphotericin B (AmBisome) in 23 patients with AIDS. AIDS. 1993;7(6):829–35.

    Article  CAS  PubMed  Google Scholar 

  89. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010;50(3):291–322.

    Article  PubMed  Google Scholar 

  90. Gangneux JP, Sulahian A, Garin YJ, Farinotti R, Derouin F. Therapy of visceral leishmaniasis due to Leishmania infantum: experimental assessment of efficacy of Am Bisome. Antimicrob Agents Chemother. 1996;40(5):1214–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Bern C, Adler-Moore J, Berenguer J, Boelaert M, den Boer M, Davidson RN, et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis. 2006;43(7):917–24.

    Article  CAS  PubMed  Google Scholar 

  92. Lewis RE, Albert ND, Liao G, Hou J, Prince RA, Kontoyiannis DP. Comparative pharmacodynamics of amphotericin B lipid complex and liposomal amphotericin B in a murine model of pulmonary mucormycosis. Antimicrob Agents Chemother. 2010;54(3):1298–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Spellberg B, Ibrahim AS, Chin-Hong PV, Kontoyiannis DP, Morris MI, Perfect JR, et al. The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial. J Antimicrob Chemother. 2012;67(3):715–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lanternier F, Lortholary O. AMBIZYGO: phase II study of high dose liposomal amphotericin B (AmBisome) [10 mg/kg/j] efficacy against zygomycosis. Med Mal Infect. 2008;38(Suppl 2):S90–1.

    Article  PubMed  Google Scholar 

  95. Johnson PC, Wheat LJ, Cloud GA, Goldman M, Lancaster D, Bamberger DM, et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med. 2002;137(2):105–9.

    Article  CAS  PubMed  Google Scholar 

  96. Wheat LJ, Cloud G, Johnson PC, Connolly P, Goldman M, Le Monte A, et al. Clearance of fungal burden during treatment of disseminated histoplasmosis with liposomal amphotericin B versus itraconazole. Antimicrob Agents Chemother. 2001;45(8):2354–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kamalaporn H, Leung K, Nagel M, Kittanakom S, Calvieri B, Reithmeier RA, et al. Aerosolized liposomal Amphotericin B: a potential prophylaxis of invasive pulmonary aspergillosis in immunocompromised patients. Pediatr Pulmonol. 2014;49(6):574–80.

    Article  PubMed  Google Scholar 

  98. Gilbert BE. Liposomal aerosols in the management of pulmonary infections. J Aerosol Med. 1996;9(1):111–22.

    Article  CAS  PubMed  Google Scholar 

  99. Monforte V, Ussetti P, López R, Gavaldà J, Bravo C, de Pablo A, et al. Nebulized liposomal amphotericin B prophylaxis for Aspergillus infection in lung transplantation: pharmacokinetics and safety. J Heart Lung Transplant. 2009;28(2):170–5.

    Article  PubMed  Google Scholar 

  100. Monforte V, Ussetti P, Gavaldà J, Bravo C, Laporta R, Len O, et al. Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation. J Heart Lung Transplant. 2010;29(5):523–30.

    Article  PubMed  Google Scholar 

  101. Rijnders BJ, Cornelissen JJ, Slobbe L, Becker MJ, Doorduijn JK, Hop WC, et al. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis. 2008;46(9):1401–8.

    Article  CAS  PubMed  Google Scholar 

  102. Purcell IF, Corris PA. Use of nebulised liposomal amphotericin B in the treatment of Aspergillus fumigatus empyema. Thorax. 1995;50(12):1321–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ramage G, VandeWalle K, Bachmann SP, Wickes BL, López-Ribot JL. In vitro pharmacodynamic properties of three antifungal agents against preformed Candida albicans biofilms determined by time-kill studies. Antimicrob Agents Chemother. 2002;46(11):3634–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Schinabeck MK, Long LA, Hossain MA, Chandra J, Mukherjee PK, Mohamed S, et al. Rabbit model of Candida albicans biofilm infection: liposomal amphotericin B antifungal lock therapy. Antimicrob Agents Chemother. 2004;48(5):1727–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Buckler BS, Sams RN, Goei VL, Krishnan KR, Bemis MJ, Parker DP, et al. Treatment of central venous catheter fungal infection using liposomal amphotericin-B lock therapy. Pediatr Infect Dis J. 2008;27(8):762–4.

    Article  PubMed  Google Scholar 

  106. Albert MM, Adams K, Luther MJ, Sun SH, Graybill JR. Efficacy of Am Bisome in murine coccidioidomycosis. J Med Vet Mycol. 1994;32(6):467–71.

    Article  CAS  PubMed  Google Scholar 

  107. Clemons KV, Stevens DA. Comparison of fungizone, Amphotec, Am Bisome, and Abelcet for treatment of systemic murine cryptococcosis. Antimicrob Agents Chemother. 1998;42(4):899–902.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Sundar S, Jha TK, Thakur CP, Mishra M, Singh VP, Buffels R. Single-dose liposomal amphotericin B in the treatment of visceral leishmaniasis in India: a multicenter study. Clin Infect Dis. 2003;37(6):800–4.

    Article  CAS  PubMed  Google Scholar 

  109. AMBITION trial. http://www.controlled-trials.com/ISRCTN10248064. Accessed 14 Jan 2016.

  110. Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW. Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med. 2010;362(6):504–12.

    Article  CAS  PubMed  Google Scholar 

  111. Sundar S, Sinha PK, Rai M, Verma DK, Nawin K, Alam S, et al. Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet. 2011;377(9764):477–86.

    Article  CAS  PubMed  Google Scholar 

  112. Khalil EA, Weldegebreal T, Younis BM, Omollo R, Musa AM, Hailu W, et al. Safety and efficacy of single dose versus multiple doses of Am Bisome for treatment of visceral leishmaniasis in eastern Africa: a randomised trial. PLoS Negl Trop Dis. 2014;8(1):e2613.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. El-Cheikh J, Faucher C, Fürst S, Duran S, Berger P, Vey N, et al. High-dose weekly liposomal amphotericin B antifungal prophylaxis following reduced-intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant. 2007;39(5):301–6.

    Article  CAS  PubMed  Google Scholar 

  114. Kelsey SM, Goldman JM, McCann S, Newland AC, Scarffe JH, Oppenheim BA, et al. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study. Bone Marrow Transplant. 1999;23(2):163–8.

    Article  CAS  PubMed  Google Scholar 

  115. Cordonnier C, Mohty M, Faucher C, Pautas C, Robin M, Vey N, et al. Safety of a weekly high dose of liposomal amphotericin B for prophylaxis of invasive fungal infection in immunocompromised patients: PROPHYSOME Study. Int J Antimicrob Agents. 2008;31(2):135–41.

    Article  CAS  PubMed  Google Scholar 

  116. Cornely O, Leguay T, Maertens J, Castagnola C, Anagnostopoulos A, Allione B, et al. A double-blind, multicentre, randomised, placebo-controlled study to assess the efficacy, safety and tolerability of prophylactic liposomal amphotericin B (AmBisome®) for the prevention of invasive fungal infections in subjects receiving remission-induction chemotherapy for acute lymphoblastic leukaemia (AmBiGuard trial). Blood. 2014;124(21):3646.

  117. Bellmann R, Egger P, Wiedermann CJ. Differences in pharmacokinetics of amphotericin B lipid formulations despite clinical equivalence. Clin Infect Dis. 2003;36(11):1500–1.

    Article  CAS  PubMed  Google Scholar 

  118. Bellmann R. Clinical pharmacokinetics of systemically administered antimycotics. Curr Clin Pharmacol. 2007;2(1):37–58.

    Article  CAS  PubMed  Google Scholar 

  119. Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev. 2014;27(1):68–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Joint Formulary Committee. British National Formulary. 70th ed. London: BMJ Group and Pharmaceutical Press;2015.

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Acknowledgments and declaration of interest

Neil Stone is supported through a Clinical Fellowship via the Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (Aberdeen University).

William Hope has acted as a consultant or received research support from Astellas Pharma, Gilead, Pfizer Inc., F2G, Pulmocide, and Basilea and is supported by a National Institutes of Health Research (NIHR) Clinician Scientist Award.

Tihana Bicanic has attended Advisory Boards for Gilead Sciences Inc and Basilea, has received sponsorship for conference attendance from Gilead Sciences Ltd and Astellas Pharma Inc., and is the co-recipient of a 2015 Gilead UK and Ireland Fellowship on Invasive Fungal Disease.

Rahuman Salim has no conflicts of interest to declare.

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Authors and Affiliations

  1. Institute for Infection and Immunity, St. George’s University of London, London, UK

    Neil R. H. Stone & Tihana Bicanic

  2. Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK

    Rahuman Salim

  3. Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, 1.09 Sherrington Building, University of Liverpool, Liverpool, UK

    William Hope

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  1. Neil R. H. Stone
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  2. Tihana Bicanic
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Correspondence to Neil R. H. Stone.

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Stone, N.R.H., Bicanic, T., Salim, R. et al. Liposomal Amphotericin B (AmBisome®): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future Directions. Drugs 76, 485–500 (2016). https://doi.org/10.1007/s40265-016-0538-7

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