Triazole Resistance in Aspergillus Species: An Emerging Problem

Abstract

Aspergillus species are ubiquitous fungal saprophytes found in diverse ecological niches worldwide. Among them, Aspergillus fumigatus is the most prevalent and is largely responsible for the increased incidence of invasive aspergillosis with high mortality rates in some immunocompromised hosts. Azoles are the first-line drugs in treating diseases caused by Aspergillus spp. However, increasing reports in A. fumigatus azole resistance, both in the clinical setting and in the environment, are threatening the effectiveness of clinical and agricultural azole drugs. The azole target is the 14-α sterol demethylase encoded by cyp51A gene and the main mechanisms of resistance involve the integration of tandem repeats in its promoter and/or single point mutations in this gene. In A. fumigatus, azole resistance can emerge in two different scenarios: a medical route in which azole resistance is generated during long periods of azole treatment in the clinical setting and a route of resistance derived from environmental origin due to extended use of demethylation inhibitors in agriculture. The understanding of A. fumigatus azole resistance development and its evolution is needed in order to prevent or minimize its impact. In this article, we review the current situation of azole resistance epidemiology and the predominant molecular mechanisms described based on the resistance acquisition routes. In addition, the clinical implications of A. fumigatus azole resistance and future research are discussed.

Azole Resistance in Aspergillus fumigatus: A Consequence of Antifungal Use in Agriculture?

“…These resistances are especially found in patients who received azole drug for a long period to treat chronic aspergillosis. Azole-resistant isolates are now identified in Norway, Spain, Belgium, Denmark, France, Germany, India, Iran, Portugal, Brazil, the Czech Republic, Turkey, Japan, Kuwait, Taiwan, Australia and China (Rivero-Menedez et al, 2016; Garcia-Rubio et al, 2017). …”

“…A wide range of cyp51A mutations were reported in both clinical and environmental isolates in Austria, Belgium, Denmark, France, Germany, Greece, Italy, The Netherlands, Poland, Portugal, Romania, Spain, Sweden, Turkey and the United Kingdom (Rivero-Menedez et al, 2016). Recently, azole resistance has also been found in Norway, Iran, Brazil, the Czech Republic, Japan, Kuwait and Taiwan (Garcia-Rubio et al, 2017). …”

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

“…However, the management of IA has become more complicated due to the emergence of azole resistance in A. fumigatus (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Surveillance studies indicate that azole resistance is increasing in Europe, the Middle East, Asia, Africa, and Australia and, most recently, in North and South America as well (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Azole-resistant IA has been shown to be associated with a very high mortality rate; therefore, alternative treatment regimens need to be investigated to improve the outcome of patients (18,31,32).…”

Analysis of RPA190 revealed multiple positively selected mutations associated with metalaxyl resistance in Phytophthora infestans

“…Like many other ecological traits, fungicide resistance can originate independently in isolated populations 7 or appear once and then spread globally by gene flow. 48,49 The evolutionary relationship of metalaxyl resistance in the current and pre-1990 collections wileyonlinelibrary.com/journal/ps showed by the haplotype network suggests that V1476G evolved independent of the other mutations; the same pattern was found by phylogenetic analysis. Furthermore, the RAA2 carrying five mutations from the Netherlands was closest evolutionarily to SAA which was also collected before 1990, whereas other sequences from the current study clustered separately.…”

“…Like many other ecological traits, fungicide resistance can originate independently in isolated populations or appear once and then spread globally by gene flow . The evolutionary relationship of metalaxyl resistance in the current and pre‐1990 collections showed by the haplotype network suggests that V1476G evolved independent of the other mutations; the same pattern was found by phylogenetic analysis.…”