TECHNICAL REPORT Risk assessment on the impact of environmental usage of triazoles on the development and spread of resistance to medical triazoles in Aspergillus species

Acknowledgements ECDC would like to thank the members of the expert panel for the contributions and comments. environmental usage of triazoles on the development and spread of resistance to medical triazoles in Aspergillus Impact of environmental usage of triazoles on development of resistance to medical triazoles in Aspergillus spp. Impact of environmental usage of triazoles on development of resistance to medical triazoles in Aspergillus spp. Abbreviations ABPA Allergic bronchopulmonary aspergillosis AML Acute myeloid leukaemia CF Cystic fibrosis COPD Chronic obstructive pulmonary disease CNS Central nervous system CPA Chronic pulmonary aspergillosis cyp51 Cytochrome P450 14-α sterol demethylase gene (gene coding for a demethylase enzyme in the ergosterol biosynthesis pathway) DMI Demethylation inhibitors EBMT HSCT Haematopoietic stem cell transplant IA Invasive aspergillosis ICU Intensive care unit MIC Minimal inhibitory concentration MSG US Mycoses Study Group PCR Polymerase chain reaction SAFS Severe asthma with fungal sensitisation TR 34 /L98H Resistance mechanism based on a 34-base pair tandem repeat in the gene promoter combined with a point mutation in the cyp51A gene at codon 98 leading to an amino acid change TB Tuberculosis Impact of environmental usage of triazoles on development of resistance to medical triazoles in Aspergillus spp. In recent years, triazole resistance in human Aspergillus diseases appears to have been increasing in several European countries. However, current data on the prevalence of resistance are based on a small number of studies which are only available from a few European countries. If present, triazole resistance can severely limit treatment options since alternatives, which are only available in intravenous form, have been shown to be associated with more side effects and poorer outcomes. Triazole resistance in Aspergillus spp. can evolve during therapy. Several point 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 have a particular genetic alteration consisting of a 34-base pair tandem repeat in the promoter coupled with a point mutation in the cyp51A target gene. This leads to an amino-acid substitution at codon 98 (TR 34 /L98H) causing multi-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 taken before the start of therapy or during an earlier phase. To date however, no isogenic isolate with a wild-type phenotype has been recovered from …