Randomised Comparison of Safety Profile and Short Term Response of Itraconazole, Voriconazole and Amphotericin B in the Management of Chronic Invasive Fungal Rhinosinusitis


Chronic invasive fungal rhino sinusitis (CIFS) is a well described clinical entity characterized by mucosal and sub mucosal infiltration of mycotic organisms and angio-centric extension into orbital and intracranial structures. Itraconazole, Voriconazole and Amphotericin B are commonly used for CIFS. In the present study we have evaluated short term clinical response of these drugs. Thirty diagnosed patients of CIFS who presented to us from January 2011 to December 2015 were divided into three groups randomly. Group A, B and C received Itraconazole, Voriconazole and Amphotericin respectively. Visual Analogue scale (VAS), Lund Mackay (LM) radiological scores and Kupferberg’s nasal endoscopic grades were seen and compared in all patients before treatment, after primary surgical debridement and biopsy and after post biopsy antifungal drug treatment. We assessed the serum drug levels using HPLC assay at 4 and 8 weeks of therapy and correlated them for efficacy and safety. All the groups had significant improvement after treatment compared to beginning of study. Inter group comparison showed that mean LM, NE and VAS scores were significantly better in Voriconazole group compared to Itraconazole and amphotericin B therapy. The reduction of these objective parameters with treatment was also significantly high in Voriconazole group compared to the other two groups. Voriconazole has shown to be the most effective treatment modality for chronic invasive fungal sinusitis compared to other commonly used drugs such as Itraconazole and Amphotericin B.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Basan C III (1991) Fungal infections of the brain. Neuroimaging Clin N Am 1:578

    Google Scholar 

  2. 2.

    de Shazo RD, Chapin K, Swain RE (1997) Fungal sinusitis. N Engl J Med 337(4):254–259. https://doi.org/10.1056/nejm199707243370407

    Article  Google Scholar 

  3. 3.

    Denning DW (1998) Invasive aspergillosis. Clin Infect Dis 26(4):781–803

    CAS  Article  Google Scholar 

  4. 4.

    Mullins J, Harvey R, Seaton A (1976) Sources and incidence of airborne Aspergillus fumigatus (Fres). Clin Allergy 6(3):209–217

    CAS  Article  Google Scholar 

  5. 5.

    Nolard N, Detandt M, Beguin H (1988) Ecology of Aspergillus species in the human environment. In: Vanden Bossche H, Mackenzie DWR, Cauwenbergh G (eds) Aspergillus and aspergillosis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-3505-2_4

    Google Scholar 

  6. 6.

    Gugnani HC (2003) Ecology and taxonomy of pathogenic aspergilli. Front Biosci J Virtual Libr 8:s346–s357

    CAS  Article  Google Scholar 

  7. 7.

    Pagella F, De Bernardi F, Dalla Gasperina D, Pusateri A, Matti E, Avato I et al (2016) Invasive fungal rhinosinusitis in adult patients: our experience in diagnosis and management. J Cranio-Maxillo-Fac Surg 44(4):512–520. https://doi.org/10.1016/j.jcms.2015.12.016

    Article  Google Scholar 

  8. 8.

    Lestner JM, Roberts SA, Moore CB, Howard SJ, Denning DW, Hope WW (2009) Toxicodynamics of itraconazole: implications for therapeutic drug monitoring. Clin Infect Dis 49(6):928–930. https://doi.org/10.1086/605499

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O (2008) Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 46(2):201–211. https://doi.org/10.1086/524669

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Lund VJ, Mackay IS (1993) Staging in rhinosinusitus. Rhinology 31(4):183–184

    CAS  PubMed  Google Scholar 

  11. 11.

    Kupferberg SB, Bent JP 3rd, Kuhn FA (1997) Prognosis for allergic fungal sinusitis. Otolaryngol Head Neck Surg 117(1):35–41. https://doi.org/10.1016/s0194-59989770203-1

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Chakrabarti A, Denning DW, Ferguson BJ, Ponikau J, Buzina W, Kita H et al (2009) Fungal rhinosinusitis: a categorization and definitional schema addressing current controversies. Laryngoscope 119(9):1809–1818. https://doi.org/10.1002/lary.20520

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Alrajhi AA, Enani M, Mahasin Z, Al-Omran K (2001) Chronic invasive aspergillosis of the paranasal sinuses in immunocompetent hosts from Saudi Arabia. Am J Trop Med Hyg 65(1):83–86

    CAS  Article  Google Scholar 

  14. 14.

    Khan A, Ali F, Imran N, Khan N, Din S (2009) Invasive sino-orbital aspergillosis in immunocompetent host. J Med Sci 17(2):87–91

    Google Scholar 

  15. 15.

    Clancy CJ, Nguyen MH (1998) Invasive sinus aspergillosis in apparently immunocompetent hosts. J Infect 37(3):229–240

    CAS  Article  Google Scholar 

  16. 16.

    Panda NK, Sharma SC, Chakrabarti A, Mann SB (1998) Paranasal sinus mycoses in north India. Mycoses 41(7–8):281–286

    CAS  Article  Google Scholar 

  17. 17.

    Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW et al (2002) Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 347(6):408–415. https://doi.org/10.1056/NEJMoa020191

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Schwartz S, Ruhnke M, Ribaud P, Reed E, Troke P, Thiel E (2007) Poor efficacy of amphotericin B-based therapy in CNS aspergillosis. Mycoses 50(3):196–200. https://doi.org/10.1111/j.1439-0507.2007.01345.x

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Park SH, Choi SM, Lee DG, Choi JH, Yoo JH, Min WS et al (2006) Intravenous itraconazole vs. amphotericin B deoxycholate for empirical antifungal therapy in patients with persistent neutropenic fever. Korean J Intern Med 21(3):165–172

    CAS  Article  Google Scholar 

  20. 20.

    Cadena J, Levine DJ, Angel LF, Maxwell PR, Brady R, Sanchez JF et al (2009) Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness. Am J Transplant 9(9):2085–2091. https://doi.org/10.1111/j.1600-6143.2009.02734.x

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose PG et al (2006) Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 50(4):1570–1572. https://doi.org/10.1128/AAC.50.4.1570-1572.2006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Kshirsagar N, Kirodian B (2002) Liposomal drug delivery system from laboratory to patients: our experience. Proc Indian Natl Sci Acad Part B 68(4):333–348

    CAS  Google Scholar 

Download references

Author information




SD: Part of the MS thesis of the author. Took part in the management of the patients, collected data and analysed. RG: Conceptualised and mentored the study and finalised the manuscript. SKP: Did Statistical analysis and interpretation of the data, prepared the manuscript and finalized the current manuscript. AKG: Mentoring of the study along with active guidance to Dr SD in this study and the thesis to which this study is a part to. PP: Conceptualisation of the study and supervising the serum drug level analysis in the study. NS: Analysis of the serum samples, analysis and interpretation of the experimental results. She has guided the first author to carry out the pharmacological analyses as a part of the study.

Corresponding author

Correspondence to Rijuneeta Gupta.

Ethics declarations

Conflict of interest

There are no conflicts of interests among authors and no financial disclosures to be made.

Ethical Approval

The research involved human participants and was done as a part of the thesis of the first author. Hence approval was taken from institutional ethical review board for conducting the study.

Informed Consent

Detailed informed consent regarding the study, possible therapeutic options, outcomes and the possible adverse effects that might arise out of the drug treatment was taken from each participant. A separate consent was also taken from patients receiving amphotericin B therapy mentioning long term in hospital stay, continuous iv therapy and need of central venous catheterization and its complications.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Debbarma, S., Gupta, R., Patro, S.K. et al. Randomised Comparison of Safety Profile and Short Term Response of Itraconazole, Voriconazole and Amphotericin B in the Management of Chronic Invasive Fungal Rhinosinusitis. Indian J Otolaryngol Head Neck Surg 71, 2165–2175 (2019). https://doi.org/10.1007/s12070-019-01602-4

Download citation


  • Chronic invasive fungal sinusitis
  • CIFS, treatment of CIFS
  • Short term response of antifungals
  • Antifungals in CIFS