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International Journal of Clinical Pharmacy

, Volume 34, Issue 4, pp 611–617 | Cite as

Evaluating real-life clinical and economical burden of amphotericin-B deoxycholate adverse reactions

  • Ehud HorwitzEmail author
  • Oren Shavit
  • Rivka Shouval
  • Amnon Hoffman
  • Mervyn Shapiro
  • Allon E. Moses
Research Article

Abstract

Background Amphotericin-B (AMB) is associated with toxicity such as renal impairment, hypokalemia and infusion-related events (IRE). With the advent of AMB lipid formulations and newer antifungal drugs, presenting improved safety profiles, it was suggested that using the conventional deoxycholate (AMB-D) formulation should no longer be regarded acceptable. Objectives Evaluation of real-life incidence of AMB-D-related adverse-drug effects (ADE) and associated costs. Setting Hadassah Hebrew University Medical Center, Jerusalem, Israel, a tertiary 1,100-bed teaching hospital. Methods A 1-year single-center prospective observational study following all patients administered AMB-D. Various parameters related to AMB-D administration were recorded. Main outcome measures Subsequent ADE-related events, discontinuations, switch to alternative antifungals and related resource-utilization were monitored. Results Among 119 patients (60 children, 59 adults) receiving AMB-D, serum creatinine doubling from baseline, hypokalemia and IRE occurred in 14.3 % (15 % in children, 13.6 % in adults), 16.8 % (16.6 % in children, 16.9 % in adults) and 10.9 % (10 % in children, 11.8 % in adults), respectively. AMB-D was discontinued due to an ADE in 12.6 % of patients (6.7 % in children, 18.6 % in adults). The total annual cost associated with AMB-D use was €58,600. Conclusion The clinical as well as economic burden of AMB-D associated ADE, as observed in real-life settings, appears to be manageable. Considering the significant cost implications associated, as suggested by simulated evaluation of an overall theoretic replacement of AMB-D by an equivalent volume of alternative antifungals, total abandonment of AMB-D appears unjustified.

Keywords

Adverse-effects Amphotericin-B Antifungals Cost-effectiveness Israel Resource utilization 

Notes

Acknowledgments

None.

Funding

None.

Conflicts of interest

None to declare [O. S. has disclosed being employed by Merck-Israel, Distributor of caspofungin (Cancidas)®, beginning after completion of data collection and analysis].

References

  1. 1.
    Ellis D. Amphotericin B: spectrum and resistance. J Antimicrob Chemother. 2002;49(Suppl 1):7–10.PubMedCrossRefGoogle Scholar
  2. 2.
    Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. Br Med J. 2001;322:579–82.CrossRefGoogle Scholar
  3. 3.
    Mayer J, Doubek M, Doubek J, Horky D, Scheer P, Stepanek M. Reduced nephrotoxicity of conventional amphotericin B therapy after minimal nephroprotective measures: animal experiments and clinical study. J Infect Dis. 2002;186:379–88.PubMedCrossRefGoogle Scholar
  4. 4.
    Torrado JJ, Espada R, Ballesteros MP, Torrado-Santiago S. Amphotericin B formulations and drug targeting [review]. J Pharm Sci. 2008;97:2405–25.PubMedCrossRefGoogle Scholar
  5. 5.
    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.PubMedGoogle Scholar
  6. 6.
    Cagnoni PJ. Liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients. J Antimicrob Chemother. 2002;49(Suppl 1):81–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Kleinberg M. What is the current and future status of conventional amphotericin B? Int J Antimicrob Agents. 2006;27(Suppl 1):12–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Miller CB, Waller EK, Klingemann HG, Dignani MC, Anaissie EJ, Cagnoni PJ, et al. Lipid formulations of amphotericin B preserve and stabilize renal function in HSCT recipients. Bone Marrow Transplant. 2004;33:543–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Saliba F, Dupont B. Renal impairment and amphotericin B formulations in patients with invasive fungal infections [review]. Med Mycol. 2008;46:97–112.PubMedCrossRefGoogle Scholar
  10. 10.
    Subira M, Martino R, Gomez L, Marti JM, Estany C, Sierra J. Low-dose amphotericin B lipid complex vs. conventional amphotericin B for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies—a randomized, controlled trial. Eur J Haematol. 2004;72:342–7.PubMedCrossRefGoogle Scholar
  11. 11.
    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;340:764–71.PubMedCrossRefGoogle Scholar
  12. 12.
    Barrett JP, Vardulaki KA, Conlon C, Cooke J, Daza-Ramirez P, Evans EJ, et al. A systematic review of the antifungal effectiveness and tolerability of amphotericin B formulations [review]. Clin Ther. 2003;25:1295–320.PubMedCrossRefGoogle Scholar
  13. 13.
    Spellberg B, Witt MD, Beck CK. Amphotericin B: is a lipid-formulation gold standard feasible [letter]? Clin Infect Dis. 2004;38:304–5. author reply 6–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Bates DW, Su L, Yu DT, Chertow GM, Seger DL, Gomes DR, et al. Mortality and costs of acute renal failure associated with amphotericin B therapy. Clin Infect Dis. 2001;32:686–93.PubMedCrossRefGoogle Scholar
  15. 15.
    Cagnoni PJ, Walsh TJ, Prendergast MM, Bodensteiner D, Hiemenz S, Greenberg RN, et al. Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients. J Clin Oncol. 2000;18:2476–83.PubMedGoogle Scholar
  16. 16.
    Harbarth S, Burke JP, Lloyd JF, Evans RS, Pestotnik SL, Samore MH. Clinical and economic outcomes of conventional amphotericin B-associated nephrotoxicity. Clin Infect Dis. 2002;35:e120–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Garbino J, Markham L, Matulionyte R, Rives V, Lew D. Should we continue using amphotericin B deoxycholate for the treatment of fungal infections? Adverse events and clinical outcomes. Scand J Infect Dis. 2006;38:110–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Ostrosky-Zeichner L, Marr KA, Rex JH, Cohen SH. Amphotericin B: time for a new “gold standard”. Clin Infect Dis. 2003;37:415–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Girmenia C, Gentile G, Micozzi A, Martino P. Nephrotoxicity of amphotericin B desoxycholate [letter]. Clin Infect Dis. 2001;33:915–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Mayer J, Doubek M, Vorlicek J. Must we really fear toxicity of conventional amphotericin B in oncological patients? Support Care Cancer. 1999;7:51–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Oto OA, Paydas S, Disel U, Yavuz S, Seydaoglu G. Amphotericin B deoxycholate (d-AMB) use in cases with febrile neutropenia and fungal infections: lower toxicity with suitable premedication. Mycoses. 2007;50:135–9.PubMedCrossRefGoogle Scholar
  22. 22.
    O’Connell B, Craig JI, Marcus RE, Ludlam H. Cost-effective use of liposomal amphotericin B. Clin Lab Haematol. 2002;24:317–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–35.PubMedCrossRefGoogle Scholar
  24. 24.
    Wingard JR. Empirical antifungal therapy in treating febrile neutropenic patients. Clin Infect Dis. 2004;39(Suppl 1):S38–43.PubMedCrossRefGoogle Scholar
  25. 25.
    Sharkey I, Boddy AV, Wallace H, Mycroft J, Hollis R, Picton S. Body surface area estimation in children using weight alone: application in paediatric oncology. Br J Cancer. 2001;85:23–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Turkova A, Roilides E, Sharland M. Amphotericin B in neonates: deoxycholate or lipid formulation as first-line therapy—is there a ‘right’ choice? Curr Opin Infect Dis. 2011;24:163–71.PubMedCrossRefGoogle Scholar
  27. 27.
    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;46:327–60.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Ehud Horwitz
    • 1
    • 2
    Email author
  • Oren Shavit
    • 2
  • Rivka Shouval
    • 1
  • Amnon Hoffman
    • 2
  • Mervyn Shapiro
    • 3
    • 4
  • Allon E. Moses
    • 3
  1. 1.Pharmacy DivisionHadassah-Hebrew University Medical CenterJerusalemIsrael
  2. 2.Department of Pharmaceutics, Faculty of Medicine, School of PharmacyThe Hebrew UniversityJerusalemIsrael
  3. 3.Department of Clinical Microbiology and Infectious DiseasesHadassah-Hebrew University Medical CenterJerusalemIsrael
  4. 4.Unit of Infectious DiseasesTel-Aviv Sourasky Medical CenterTel AvivIsrael

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