Comment on: Low prevalence of resistance to azoles in Aspergillus fumigatus in a French cohort of patients treated for haematological malignancies.

Sir, Azole resistance is an emerging clinical problem in patients with Aspergillus infections, primarily those caused by Aspergillus fumigatus. Alanio et al. describe the results of a study that investigated the prevalence of azole resistance in 118 clinical Aspergillus isolates obtained from a cohort of 89 patients with haematological malignancy. They found only one azole-resistant A. fumigatus isolate, which corresponded to a prevalence of 0.85%. Although the low prevalence of resistance may be reassuring, the circumstances surrounding the resistant isolate are a cause of great concern. The azole-resistant isolate was cultured from an azole-naive patient, which precludes resistance development through azole therapy. The only other possibility is that the patient acquired the resistant isolate from the environment, as A. fumigatus is a saprophytic mould and patient-topatient transmission of aspergilli is highly unlikely. The probability of an environmental source for the azole-resistant isolate was further increased by the resistance mechanism that was found. As indicated by the authors, the position of the substitution in the CYP51A gene was similar to that found in Mycosphaerella graminicola, an important phytopathogenic mould that significantly affects wheat throughout Europe and is almost exclusively controlled with sterol 14a-demethylation inhibitors (DMIs). The similarity of the resistance mechanisms suggests that both moulds developed the mutation in response to exposure to the same compound. As both moulds share the same niche in the environment, this is the most feasible scenario. In the Netherlands there is increasing evidence that a resistance mechanism involving two genomic changes, a substitution at codon 98 of the CYP51A gene and the insertion of a tandem repeat in the gene promoter (TR/L98H), has emerged through exposure to DMIs. Clinical isolates harbouring this resistance mechanism show decreased susceptibility to the medical azoles itraconazole, posaconazole and voriconazole and were first found in 1998. Since then, an increasing prevalence over time has been observed, and such isolates now account for between 6% and 12.8% of clinical A. fumigatus isolates. Isolates containing the TR/L98H resistance mechanism were also cultured from environmental sources in the Netherlands, and were found to be crossresistant to certain DMIs. Surveillance studies indicated that TR/L98H is now endemic in the Netherlands, and recently the same resistance mechanism was found in environmental A. fumigatus isolates in Denmark. It has been difficult to explain why azole resistance has emerged in the Netherlands, but apparently not in other European countries despite similar crop protection practices using the same DMIs. The significance of the observation of Alanio et al. is that their study suggests that the environmental route of resistance development is not restricted to the Netherlands, but has also taken place in another country and with the emergence of a new resistance mechanism. The recovery of A. fumigatus isolates harbouring G432S from the environment would confirm the environmental route of resistance development. The Dutch experience with TR/L98H shows that rapid spread and an increasing prevalence of resistant isolates can be expected if the acquisition of the resistance mechanism is not associated with a fitness cost. Patients with azole-resistant Aspergillus diseases commonly fail azole therapy and resistance significantly complicates their management. Furthermore, it can be anticipated that, unless effective measures are taken, the continued use of DMIs will result in the emergence of multiple resistance mechanisms in the countries that use these fungicides. A policy aimed at precluding the environmental route of resistance development requires more research into the relation between DMI use and resistance development to medical triazoles. The authors propose to perform surveillance studies, but these should not be limited to clinical Aspergillus isolates and should also include field isolates. Furthermore, surveillance studies should be performed in all countries with substantial DMI use and coordinated at the European level.