Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Infectious Complications

Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT

Abstract

The aim of this study was to assess the frequency of potential drug–drug interactions (pDDIs) and adverse drug events (ADEs) associated with antimycotics in hospitalized patients with hematopoietic SCT (HSCT). Of the 120 HSCT recipients evaluated, 36 received antimycotics. A total of 124 ADEs were recorded in 32 of the 36 patients treated, with 54 ADEs being possibly and 9 probably related to antimycotics. Of the treatments with amphotericin B, 93% were associated with one or more possible and 36% with probable ADEs. The corresponding figures for lipid-based amphotericin B were 100% and 7%, for voriconazole 68% and 11% and for caspofungin 70% and 0%. A total of 57 potentially severe DDIs associated with antimycotics were detected in 31 of the 36 patients. Of these, 14 DDIs were a possible cause of an ADE and 5 (4 times a combination of voriconazole with CYA and once a combination of CYA with conventional amphotericin B) were probably related. Although the prevalence of pDDIs and ADEs is high in HSCT patients, ADEs related with a high probability to treatment with antimycotics are rare. Regarding the high prevalence of pDDIs, our findings underscore the importance of close monitoring of laboratory and clinical parameters, as well as dose adjustment for critical drugs, in patients with HSCT.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Singh N, Paterson DL . Aspergillus infections in transplant recipients. Clin Microbiol Rev 2005; 18: 44–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fluckiger U, Marchetti O, Bille J, Eggimann P, Zimmerli S, Imhof A et al. Treatment options of invasive fungal infections in adults. Swiss Med Wkly 2006; 136: 447–463.

    CAS  PubMed  Google Scholar 

  3. Ruping MJ, Vehreschild JJ, Cornely OA . Patients at high risk of invasive fungal infections: when and how to treat. Drugs 2008; 68: 1941–1962.

    Article  PubMed  Google Scholar 

  4. 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 

  5. Bekersky II, Fielding RM, Buell D, Lawrence II . Lipid-based amphotericin B formulations: from animals to man. Pharm Sci Technolo Today 1999; 2: 230–236.

    Article  CAS  Google Scholar 

  6. Ostrosky-Zeichner L . Combination antifungal therapy: a critical review of the evidence. Clin Microbiol Infect 2008; 14 (Suppl 4): 65–70.

    Article  CAS  PubMed  Google Scholar 

  7. Chen SC, Sorrell TC . Antifungal agents. Med J Aust 2007; 187: 404–409.

    PubMed  Google Scholar 

  8. Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK . Adverse drug reactions. BMJ 1998; 316: 1295–1298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Niwa T, Shiraga T, Takagi A . Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull 2005; 28: 1805–1808.

    Article  CAS  PubMed  Google Scholar 

  10. Nivoix Y, Leveque D, Herbrecht R, Koffel JC, Beretz L, Ubeaud-Sequier G . The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet 2008; 47: 779–792.

    Article  CAS  PubMed  Google Scholar 

  11. Bruggemann RJ, Alffenaar JW, Blijlevens NM, Billaud EM, Kosterink JG, Verweij PE et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 2009; 48: 1441–1458.

    Article  PubMed  Google Scholar 

  12. Boucher HW, Groll AH, Chiou CC, Walsh TJ . Newer systemic antifungal agents: pharmacokinetics, safety and efficacy. Drugs 2004; 64: 1997–2020.

    Article  CAS  PubMed  Google Scholar 

  13. Lipp HP . Antifungal agents—clinical pharmacokinetics and drug interactions. Mycoses 2008; 51 (Suppl 1): 7–18.

    Article  CAS  PubMed  Google Scholar 

  14. Kauffman CA . Fungal infections in older adults. Clin Infect Dis 2001; 33: 550–555.

    Article  CAS  PubMed  Google Scholar 

  15. Kulemann V, Bauer M, Graninger W, Joukhadar C . Safety and potential of drug interactions of caspofungin and voriconazole in multimorbid patients. Pharmacology 2005; 75: 165–178.

    Article  CAS  PubMed  Google Scholar 

  16. Swiss Compendium of Drugs. Product Information Caspofungin, (online) Documed AG: Basel, Switzerland, 2009.

  17. Marr KA, Hachem R, Papanicolaou G, Somani J, Arduino JM, Lipka CJ et al. Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A. Transpl Infect Dis 2004; 6: 110–116.

    Article  CAS  PubMed  Google Scholar 

  18. Sanz-Rodriguez C, Arranz R, Cisneros JM, Garcia-Sanchez PJ, Jurado M, Lopez J et al. Absence of clinically relevant effect of caspofungin on cyclosporin pharmacokinetics. Swiss Med Wkly 2005; 135: 658–659.

    PubMed  Google Scholar 

  19. Christopeit M, Eikam M, Behre G . Comedication of caspofungin acetate and cyclosporine A after allogeneic haematopoietic stem cell transplantation leads to negligible hepatotoxicity. Mycoses 2008; 51 (Suppl 1): 19–24.

    Article  CAS  PubMed  Google Scholar 

  20. DRUG-REAX®. System [Internet database]. Thomson Healthcare: Greenwood Village, Colorado, (updated periodically).

  21. Dettli L . The kidney in pre-clinical and clinical pharmacokinetics. Jpn J Clin Pharmacol Ther 1984; 15: 241–254.

    Article  Google Scholar 

  22. Payne RB, Little AJ, Williams RB, Milner JR . Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J 1973; 4: 643–646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Duncan N, Craddock C . Optimizing the use of cyclosporin in allogeneic stem cell transplantation. Bone Marrow Transplant 2006; 38: 169–174.

    Article  CAS  PubMed  Google Scholar 

  24. Ruutu T, Niederwieser D, Gratwohl A, Apperley JF . A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow, Transplantation (EBMT). Chronic Leukaemia Working Party of the EBMT. Bone Marrow Transplant 1997; 19: 759–764.

    Article  CAS  PubMed  Google Scholar 

  25. Uppsala Monitoring Centre. Causality Assessment of Suspected Adverse Reactions. WHO Collaborating Centre for International Drug Monitoring: Uppsala, Sweden, (Accessed on 03 March 2009).

  26. Kullberg BJ, Sobel JD, Ruhnke M, Pappas PG, Viscoli C, Rex JH et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet 2005; 366: 1435–1442.

    Article  CAS  PubMed  Google Scholar 

  27. 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: 225–234.

    Article  CAS  PubMed  Google Scholar 

  28. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–415.

    Article  CAS  PubMed  Google Scholar 

  29. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002; 347: 2020–2029.

    Article  CAS  PubMed  Google Scholar 

  30. 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: 1391–1402.

    Article  CAS  PubMed  Google Scholar 

  31. Ellis M, Frampton C, Joseph J, Alizadeh H, Kristensen J, Hauggaard A et al. An open study of the comparative efficacy and safety of caspofungin and liposomal amphotericin B in treating invasive fungal infections or febrile neutropenia in patients with haematological malignancy. J Med Microbiol 2006; 55 (Pt 10): 1357–1365.

    Article  CAS  PubMed  Google Scholar 

  32. Arathoon EG, Gotuzzo E, Noriega LM, Berman RS, DiNubile MJ, Sable CA . Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother 2002; 46: 451–457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Straubhaar B, Krahenbuhl S, Schlienger RG . The prevalence of potential drug-drug interactions in patients with heart failure at hospital discharge. Drug Saf 2006; 29: 79–90.

    Article  PubMed  Google Scholar 

  34. Egger SS, Drewe J, Schlienger RG . Potential drug-drug interactions in the medication of medical patients at hospital discharge. Eur J Clin Pharmacol 2003; 58: 773–778.

    Article  PubMed  Google Scholar 

  35. Kohler GI, Bode-Boger SM, Busse R, Hoopmann M, Welte T, Boger RH . Drug-drug interactions in medical patients: effects of in-hospital treatment and relation to multiple drug use. Int J Clin Pharmacol Ther 2000; 38: 504–513.

    Article  CAS  PubMed  Google Scholar 

  36. Depont F, Vargas F, Dutronc H, Giauque E, Ragnaud JM, Galperine T et al. Drug-drug interactions with systemic antifungals in clinical practice. Pharmacoepidemiol Drug Saf 2007; 16: 1227–1233.

    Article  PubMed  Google Scholar 

  37. Yu DT, Peterson JF, Seger DL, Gerth WC, Bates DW . Frequency of potential azole drug-drug interactions and consequences of potential fluconazole drug interactions. Pharmacoepidemiol Drug Saf 2005; 14: 755–767.

    Article  CAS  PubMed  Google Scholar 

  38. Muijsers RB, Goa KL, Scott LJ . Voriconazole: in the treatment of invasive aspergillosis. Drugs 2002; 62: 2655–2664 discussion 2665–6.

    Article  CAS  PubMed  Google Scholar 

  39. Saad AH, DePestel DD, Carver PL . Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy 2006; 26: 1730–1744.

    Article  CAS  PubMed  Google Scholar 

  40. Romero AJ, Le Pogamp P, Nilsson LG, Wood N . Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther 2002; 71: 226–234.

    Article  CAS  PubMed  Google Scholar 

  41. Swiss Compendium of Drugs. Product information voriconazole, (online) Documed AG: Basel, Switzerland, 2009.

  42. Sadaba B, Campanero MA, Quetglas EG, Azanza JR . Clinical relevance of sirolimus drug interactions in transplant patients. Transplant Proc 2004; 36: 3226–3228.

    Article  CAS  PubMed  Google Scholar 

  43. Surowiec D, DePestel DD, Carver PL . Concurrent administration of sirolimus and voriconazole: a pilot study assessing safety and approaches to appropriate management. Pharmacotherapy 2008; 28: 719–729.

    Article  CAS  PubMed  Google Scholar 

  44. Marty FM, Lowry CM, Cutler CS, Campbell BJ, Fiumara K, Baden LR et al. Voriconazole and sirolimus coadministration after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006; 12: 552–559.

    Article  CAS  PubMed  Google Scholar 

  45. Saner F, Gensicke J, Rath P, Fruhauf N, Gu Y, Paul A et al. Safety profile of concomitant use of caspofungin and cyclosporine or tacrolimus in liver transplant patients. Infection 2006; 34: 328–332.

    Article  CAS  PubMed  Google Scholar 

  46. Trenschel R, Ditschkowski M, Elmaagacli AH, Koldehoff M, Ottinger H, Steckel N et al. Caspofungin as second-line therapy for fever of unknown origin or invasive fungal infection following allogeneic stem cell transplantation. Bone Marrow Transplant 2005; 35: 583–586.

    Article  CAS  PubMed  Google Scholar 

  47. Sanz-Rodriguez C, Lopez-Duarte M, Jurado M, Lopez J, Arranz R, Cisneros JM et al. Safety of the concomitant use of caspofungin and cyclosporin A in patients with invasive fungal infections. Bone Marrow Transplant 2004; 34: 13–20.

    Article  CAS  PubMed  Google Scholar 

  48. Kim BK, Chung KW, Sun HS, Suh JG, Min WS, Kang CS et al. Liver disease during the first post-transplant year in bone marrow transplantation recipients: retrospective study. Bone Marrow Transplant 2000; 26: 193–197.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Swiss National Science Foundation to SK (310000-112483).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S Krähenbühl.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Egger, S., Meier, S., Leu, C. et al. Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT. Bone Marrow Transplant 45, 1197–1203 (2010). https://doi.org/10.1038/bmt.2009.325

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2009.325

Keywords

This article is cited by

Search

Quick links