Assessing the potential antifungal resistance risk from dual use of a mode of action in agriculture and medical treatment of human pathogens.

Abstract

A mechanistic basis is described for assessment of resistance risk to medical anti-fungal treatments from agricultural use of fungicides of the same mode of action. The following need to occur in landscape environments for a risk to be posed by dual use: (i) emergence, whereby a resistant strain emerges by mutation and invasion, (ii) selection, whereby a mutation conferring a fitness advantage is selected for in the presence of fungicide, and (iii) exposure of humans to resistant strains from the landscape, potentially resulting in invasive fungal infection (IFI). We identify 20 human fungal pathogens for which there is evidence that all three processes above could, in principle, occur. A model is derived for quantitative analysis to explore what determines resistance emergence and selection in human pathogens in landscape environments. Emergence and selection were particularly affected by fitness cost associated with the resistance mutation(s) and fungicide concentration. Emergence was also determined by the amount of pathogen reproduction (related to pathogen population size). The findings were related to an example case of observational data from the Netherlands for Aspergillus fumigatus. The analysis supports previous work that compost, including bulb waste, is towards the high-risk end of the spectrum for this species. Agricultural soils, non-agricultural land and grassland were lower risk. More generally, across species, the model output suggests that if fungicide resistance is associated with even a small fitness cost, then environments with low fungicide concentrations, such as field soils and semi-natural environments (e.g. woodland), may not be conducive to resistance emergence or selection.