Antifungal Cross-Resistance and the need for an antifungal resistance database

by Oscar Megan

Triazole resistance in Aspergillus fumigatus is an emerging health problem. This fungus is a major cause of invasive fungal infections in immunocompromised individuals, and has spread significantly in the last decades (Zhang et al., 2017). There are two main classes of antifungals used to treat this fungal infection: (1) Medical triazoles, used for cases of human infection (For example, Itraconazole and posaconazole). (2) Sterol-Biosynthesis Inhibitors used as agricultural fungicides (Used in the treatment of wood fences, or decaying plant matter). There are two presumed paths to medical triazole resistance: (1) Through selection pressure of triazole use
when treating patients. (2) Through selection pressure of non-medical SIs used in the environment. Put simply, Aspergillus fumigatus is also presumed to develop medical triazole resistance when only exposed to the non-medical sterol-biosynthesis inhibitors (SIs).

In a 2017 study (Zhang et al., 2017), researchers sought out to determine the level, and speed at which this cross-resistance is developed in Aspergillus fumigatus. Evolved Aspergillus fumigatus samples were used from a previous study which tested for SI resistance for five different agricultural fungicides. In the 2017 study, these evolved lineages were then exposed to three medical Triazoles (1)itraconazole (2)posaconazole (3) voriconazole over seven weeks
at varying concentrations to determine the minimal inhibitory concentration (MIC) for the evolved lineages.

These figures show the change in relative MIC over time. Plot (a) shows the results of the previous study, plots (b), (c) and (d) show the changes when exposed to the three medical Triazoles.

The observable trend from these figures is that, over seven weeks the SI resistant strains develop medical triazole resistance (because of the increasing minimal inhibitory concentration). After whole-genome sequencing the now medical triazole resistant lineages, it was found that there were no structural changes needed to develop this resistance. Put simply, by developing SI resistance Aspergillus fumigatus also developed resistance to medical triazoles.

This finding is of major concern. If sterol-biosynthesis inhibitors are overused in agriculture or elsewhere, Aspergillus fumigatus could develop medical triazole resistance through selection pressures.

A similar phenomenon in antibiotics resistance has been observed in recent decades. To combat this, the antibiotic resistance database Comprehensive Antibiotic Resistance Database or CARD, was funded. CARD was made so that findings relevant to resistance could be made publicly available. Currently, there are no large-scale, well funded antifungal resistance databases, and the findings of this 2017 study highlight the growing need to fund such a database.

References:

Zhang, J., van den Heuvel, J., J. M. Debets, A., E. Verweij, P., J. G. Melchers, W., J. Zwaan, B. and E. Schoustra, S., 2017. Evolution of cross-resistance to medical triazoles in Aspergillus fumigatus through selection pressure of environmental fungicides.

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