Research article Open Access
Like 0


The prevalence of invasive aspergillosis (IA) at the intensive care unit (ICU) is unknown and difficult to assess since IA also develops in patients lacking specific host factors. In the Netherlands, increasing azole-resistance in complicates treatment of patients with IA. The aim of this study was to determine the prevalence of IA by azole-resistant at the ICU among patients receiving antifungal treatment and to follow their clinical outcome and prognosis. A retrospective cohort study was conducted in a university hospital ICU from January 2010 to December 2013. From all patients who received antifungal treatment for suspected IA, relevant clinical and microbiological data were collected using a standardised questionnaire. Of 9,121 admitted ICU-patients, 136 had received antifungal treatment for suspected IA, of which 38 had a positive culture. Ten of the 38 patients harboured at least one azole-resistant isolate. Resistance mechanisms consisted of alterations in the cyp51A gene, more specific TR/L98H and TR/T289A/Y121F. Microsatellite typing did not show clonal relatedness, though isolates from two patients were genetically related. The overall 90-day mortality of patients with IA by azole-resistant and patients with suspicion of IA by azole-susceptible isolates in the ICU was 100% (10/10) vs 82% (23/28) respectively. We conclude that the changing pattern of IA in ICU patients requires appropriate criteria for recognition, diagnosis and rapid resistance tests. The increase in azole resistance rates also challenges a reconsideration of empirical antifungal therapy.


Article metrics loading...

Loading full text...

Full text loading...



  1. Verweij PE, Snelders E, Kema GHJ, Mellado E, Melchers WJG. Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect Dis. 2009;9(12):789-95.  https://doi.org/10.1016/S1473-3099(09)70265-8  PMID: 19926038 
  2. van der Linden JWM, Camps SMT, Kampinga GA, Arends JPA, Debets-Ossenkopp YJ, Haas PJA, et al. Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles. Clin Infect Dis. 2013;57(4):513-20.  https://doi.org/10.1093/cid/cit320  PMID: 23667263 
  3. van der Linden JWM, Snelders E, Kampinga GA, Rijnders BJA, Mattsson E, Debets-Ossenkopp YJ, et al. Clinical implications of azole resistance in Aspergillus fumigatus, The Netherlands, 2007-2009. Emerg Infect Dis. 2011;17(10):1846-54.  https://doi.org/10.3201/eid1710.110226  PMID: 22000354 
  4. Vermeulen E, Lagrou K, Verweij PE. Azole resistance in Aspergillus fumigatus: a growing public health concern. Curr Opin Infect Dis. 2013;26(6):493-500.  https://doi.org/10.1097/QCO.0000000000000005  PMID: 24126719 
  5. Denning DW, Bowyer P. Voriconazole resistance in Aspergillus fumigatus: should we be concerned? Clin Infect Dis. 2013;57(4):521-3.  https://doi.org/10.1093/cid/cit321  PMID: 23667265 
  6. Steinmann J, Hamprecht A, Vehreschild MJGT, Cornely OA, Buchheidt D, Spiess B, et al. Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany. J Antimicrob Chemother. 2015;70(5):1522-6.  https://doi.org/10.1093/jac/dku566  PMID: 25630644 
  7. Chowdhary A, Kathuria S, Xu J, Meis JF. Emergence of azole-resistant aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health. PLoS Pathog. 2013;9(10):e1003633.  https://doi.org/10.1371/journal.ppat.1003633  PMID: 24204249 
  8. Chowdhary A, Sharma C, van den Boom M, Yntema JB, Hagen F, Verweij PE, et al. Multi-azole-resistant Aspergillus fumigatus in the environment in Tanzania. J Antimicrob Chemother. 2014;69(11):2979-83.  https://doi.org/10.1093/jac/dku259  PMID: 25006238 
  9. Le Pape P, Lavergne RA, Morio F, Alvarez-Moreno C. Multiple Fungicide-Driven Alterations in Azole-Resistant Aspergillus fumigatus, Colombia, 2015. Emerg Infect Dis. 2016;22(1):156-7.  https://doi.org/10.3201/eid2201.150978  PMID: 26690795 
  10. Wiederhold NP, Gil VG, Gutierrez F, Lindner JR, Albataineh MT, McCarthy DI, et al. First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States. J Clin Microbiol. 2016;54(1):168-71.  https://doi.org/10.1128/JCM.02478-15  PMID: 26491179 
  11. Meersseman W, Lagrou K, Maertens J, Van Wijngaerden E. Invasive aspergillosis in the intensive care unit. Clin Infect Dis. 2007;45(2):205-16.  https://doi.org/10.1086/518852  PMID: 17578780 
  12. Taccone FS, Van den Abeele AM, Bulpa P, Misset B, Meersseman W, Cardoso T, et al. AspICU Study Investigators. Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Crit Care. 2015;19(1):7.  https://doi.org/10.1186/s13054-014-0722-7  PMID: 25928694 
  13. De Pauw BE. Increasing fungal infections in the intensive care unit. Surg Infect (Larchmt). 2006;7(Suppl 2):S93-6. PMID: 16895517 
  14. Vandewoude KH, Blot SI, Depuydt P, Benoit D, Temmerman W, Colardyn F, et al. Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Crit Care. 2006;10(1):R31.  https://doi.org/10.1186/cc4823  PMID: 16507158 
  15. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. . Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813-21.  https://doi.org/10.1086/588660  PMID: 18462102 
  16. Blot SI, Taccone FS, Van den Abeele AM, Bulpa P, Meersseman W, Brusselaers N, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med. 2012;186(1):56-64.  https://doi.org/10.1164/rccm.201111-1978OC  PMID: 24126719 
  17. Versalovic J, Carroll KC, Funke G, Jorgensen JH, Landry ML, Warnock DW, editors. Manual of Clinical Microbiology. 10th edition. Washington, DC: ASM Press; 2011.
  18. Lass-Flörl C, Mayr A, Perkhofer S, Hinterberger G, Hausdorfer J, Speth C, et al. Activities of antifungal agents against yeasts and filamentous fungi: assessment according to the methodology of the European Committee on Antimicrobial Susceptibility Testing. Antimicrob Agents Chemother. 2008;52(10):3637-41.  https://doi.org/10.1128/AAC.00662-08  PMID: 18694949 
  19. de Valk HA, Meis JF, Curfs IM, Muehlethaler K, Mouton JW, Klaassen CH. Use of a novel panel of nine short tandem repeats for exact and high-resolution fingerprinting of Aspergillus fumigatus isolates. J Clin Microbiol. 2005;43(8):4112-20.  https://doi.org/10.1128/JCM.43.8.4112-4120.2005  PMID: 16081958 
  20. Fuhren J, Voskuil WS, Boel CH, Haas PJ, Hagen F, Meis JF, et al. High prevalence of azole resistance in Aspergillus fumigatus isolates from high-risk patients. J Antimicrob Chemother. 2015;70(10):2894-8.  https://doi.org/10.1093/jac/dkv177  PMID: 26163402 
  21. Trof RJ, Beishuizen A, Debets-Ossenkopp YJ, Girbes AR, Groeneveld AB. Management of invasive pulmonary aspergillosis in non-neutropenic critically ill patients. Intensive Care Med. 2007;33(10):1694-703.  https://doi.org/10.1007/s00134-007-0791-z  PMID: 17646966 
  22. Snelders E, Huis In ’t Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75(12):4053-7.  https://doi.org/10.1128/AEM.00231-09  PMID: 19376899 
  23. Camps SM, van der Linden JW, Li Y, Kuijper EJ, van Dissel JT, Verweij PE, et al. Rapid induction of multiple resistance mechanisms in Aspergillus fumigatus during azole therapy: a case study and review of the literature. Antimicrob Agents Chemother. 2012;56(1):10-6.  https://doi.org/10.1128/AAC.05088-11  PMID: 22005994 
  24. Ahmad S, Joseph L, Hagen F, Meis JF, Khan Z. Concomitant occurrence of itraconazole-resistant and -susceptible strains of Aspergillus fumigatus in routine cultures. J Antimicrob Chemother. 2015;70(2):412-5.  https://doi.org/10.1093/jac/dku410  PMID: 25326091 
  25. Spiess B, Seifarth W, Merker N, Howard SJ, Reinwald M, Dietz A, et al. Development of novel PCR assays to detect azole resistance-mediating mutations of the Aspergillus fumigatus cyp51A gene in primary clinical samples from neutropenic patients. Antimicrob Agents Chemother. 2012;56(7):3905-10.  https://doi.org/10.1128/AAC.05902-11  PMID: 22526309 
  26. Chong GLM, van de Sande WW, Dingemans GJH, Gaajetaan GR, Vonk AG, Hayette MP, et al. Validation of a new Aspergillus real-time PCR assay for direct detection of Aspergillus and azole resistance of Aspergillus fumigatus on bronchoalveolar lavage fluid. J Clin Microbiol. 2015;53(3):868-74.  https://doi.org/10.1128/JCM.03216-14  PMID: 25568431 
  27. White PL, Posso RB, Barnes RA. Analytical and clinical evaluation of the pathoNostics AsperGenius assay for detection of invasive aspergilosis and resistance to azole antifungal drugs during testing of serum samples. J Clin Microbiol. 2015;53(7):2115-21.  https://doi.org/10.1128/JCM.00667-15  PMID: 25903571 
  28. Verweij PE, Ananda-Rajah M, Andes D, Arendrup MC, Brüggemann RJ, Chowdhary A, et al. International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus. Drug Resist Updat. 2015;21-22:30-40.  https://doi.org/10.1016/j.drup.2015.08.001  PMID: 26282594 
  29. Seyedmousavi S, Melchers WJ, Mouton JW, Verweij PE. Pharmacodynamics and dose-response relationships of liposomal amphotericin B against different azole-resistant Aspergillus fumigatus isolates in a murine model of disseminated aspergillosis. Antimicrob Agents Chemother. 2013;57(4):1866-71.  https://doi.org/10.1128/AAC.02226-12  PMID: 23380732 
  30. Seyedmousavi S, Brüggemann RJM, Melchers WJ, Rijs AJ, Verweij PE, Mouton JW. Efficacy and pharmacodynamics of voriconazole combined with anidulafungin in azole-resistant invasive aspergillosis. J Antimicrob Chemother. 2013;68(2):385-93.  https://doi.org/10.1093/jac/dks402  PMID: 23129729 
  31. Seyedmousavi S, Mouton JW, Melchers WJG, Brüggemann RJM, Verweij PE. The role of azoles in the management of azole-resistant aspergillosis: from the bench to the bedside. Drug Resist Updat. 2014;17(3):37-50.  https://doi.org/10.1016/j.drup.2014.06.001  PMID: 25066814 
  32. Siopi M, Mavridou E, Mouton JW, Verweij PE, Zerva L, Meletiadis J. Susceptibility breakpoints and target values for therapeutic drug monitoring of voriconazole and Aspergillus fumigatus in an in vitro pharmacokinetic/pharmacodynamic model--authors’ response. J Antimicrob Chemother. 2015;70(2):634-5.  https://doi.org/10.1093/jac/dku484  PMID: 25488075 

Data & Media loading...

Submit comment
Comment moderation successfully completed
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error