Risk assessment on the impact of environmental usage of triazoles on the development and spread of resistance to medical triazoles in Aspergillus species. Stockholm: ECDC; 2013

Research output: Book/ReportCommissioned report

  • External authors:
  • Niels Kleinkauf
  • Paul E. Verweij
  • Maiken C. Arendrup
  • Peter J. Donnelly
  • Manuel Cuenca-Estrella
  • Bart Fraaije
  • Willem J.G. Melchers
  • Niels Adriaenssens
  • Gert H.J. Kema
  • Andrew Ullmann


In recent years, triazole resistance in human Aspergillus diseases appears to have been increasing in severalEuropean countries. However, current data on the prevalence of resistance are based on a small number of studieswhich are only available from a few European countries. If present, triazole resistance can severely limit treatmentoptions since alternatives, which are only available in intravenous form, have been shown to be associated withmore side effects and poorer outcomes. Triazole resistance in Aspergillus spp. can evolve during therapy. Severalpoint mutations, particularly in the cyp51A gene, have been associated with the development of resistance.Increasingly however, resistant isolates are also being detected in azole-naive patients. These isolates tend to havea particular genetic alteration consisting of a 34-base pair tandem repeat in the promoter coupled with a pointmutation in the cyp51A target gene. This leads to an amino-acid substitution at codon 98 (TR34/L98H) causingmulti-azole resistance. In patients whose Aspergillus isolates have developed resistance during azole therapy wild-type isolates, closely related genetically to the resistant isolates, have regularly been recovered from samples takenbefore the start of therapy or during an earlier phase. To date however, no isogenic isolate with a wild-typephenotype has been recovered from patients infected with an Aspergillus strain carrying the TR34/L98H geneticalteration. This suggests a possible environmental origin of the resistant fungus. This particular resistancemechanism has been observed most frequently in clinical isolates in the Netherlands where it has also been foundin the environment. Moreover, the resistance mechanism has been demonstrated in clinical isolates in eight otherEuropean countries.Azole fungicides are widely used for crop protection and material preservation in Europe. They protect crops fromdisease, ensure yields and prevent fungal contamination of produce. It has been proposed that triazole resistancehas evolved in the environment and could be driven by the selective pressure of azole fungicides. Althoughevidence supporting this hypothesis is growing, the link between the environmental use of azole fungicides and thedevelopment of triazole resistance in Aspergillus spp. is not yet proven.Triazole therapy has become the established treatment for invasive aspergillosis and is widely used in thetreatment of allergic aspergillosis and chronic pulmonary aspergillosis. Antifungal therapy for invasive pulmonaryaspergillosis is usually prescribed for a minimum of 6–12 weeks, but often may need to be continued for monthsdepending on the period of immunosuppression. Treatment of allergic aspergillosis and chronic pulmonaryaspergillosis may need to continue for years or even throughout a patient’s lifetime. We estimated the burden ofallergic, chronic and invasive aspergillosis using population statistics and published literature. Of the 733 millioninhabitants in the European region 1 [1], at any one time 2 100 000 patients may be suffering from allergicaspergillosis and 240 000 from chronic aspergillosis, that would be an indication for antifungal therapy. For invasiveaspergillosis, we have estimated an annual incidence of 63 250 cases, complicating multiple underlying conditionsincluding leukaemia, transplantation, chronic obstructive pulmonary disease (COPD) and medical intensive care.The inability to treat these patients with triazoles due to multi-azole resistance would have significant impact onpatient management and associated health costs.Early and thorough investigation of this emerging public health problem is warranted in order to avoid thedevelopment and spread of resistance. This report examines current evidence for the environmental origin ofresistance in Aspergillus spp. and makes recommendations for further steps to assess the risks and consequencesof the environmental usage of azole derivatives. Improved surveillance of clinical isolates, including antifungalsusceptibility testing, is the key to a better understanding of the magnitude of this emerging problem. Furthermore,the diagnosis of Aspergillus diseases needs to be improved and molecular methods allowing detection of resistancein culture-negative specimens must be further developed and implemented in laboratory practice. Finally, furtherenvironmental and laboratory studies are needed to confirm the environmental hypothesis.

Bibliographical metadata

Original languageEnglish
Place of PublicationStockholm
PublisherEuropean Centre for Disease Prevention and Control
Publication statusPublished - Feb 2013

Publication series

NameEuropean Centre for Disease Prevention and Control Technical Report
PublisherEuropean Centre for Disease Control