Epidemiological Studies of Pan-Azole Resistant Aspergillus fumigatus Populations Sampled during Tulip Cultivation Show Clonal Expansion with Acquisition of Multi-Fungicide Resistance as Potential Driver.

Bart A Fraaije,Sarah L Atkins,Jonathan S West,Steven J Hanley,John A Lucas,Ricardo F Santos

doi:10.3390/microorganisms9112379

Abstract

Pan-azole resistant isolates are found in clinical and environmental Aspergillus fumigatus (Af) populations. Azole resistance can evolve in both settings, with Af directly targeted by antifungals in patients and, in the environment, Af unintendedly exposed to fungicides used for material preservation and plant disease control. Resistance to non-azole fungicides, including methyl benzimidazole carbamates (MBCs), quinone outside inhibitors (QoIs) and succinate dehydrogenase inhibitors (SDHIs), has recently been reported. These fungicide groups are not used in medicine but can play an important role in the further spread of pan-azole resistant genotypes. We investigated the multi-fungicide resistance status and the genetic diversity of Af populations sampled from tulip field soils, tulip peel waste and flower compost heaps using fungicide sensitivity testing and a range of genotyping tools, including STRAf typing and sequencing of fungicide resistant alleles. Two major clones were present in the tulip bulb population. Comparisons with clinical isolates and literature data revealed that several common clonal lineages of TR34/L98H and TR46/Y121F/T289A strains that have expanded successfully in the environment have also acquired resistance to MBC, QoI and/or SDHI fungicides. Strains carrying multiple fungicide resistant alleles have a competitive advantage in environments where residues of multiple fungicides belonging to different modes of action are present.

Highlights

Airborne Aspergillus fumigatus (Af ) spores can, after inhalation, cause disease in animals and humans ranging from allergic conditions and chronic lung infection to acute invasive aspergillosis (IA)
Two TR34 /L98H isolates, ARAF017 and CYP_15_46, were insensitive to fungicides belonging to all four different modes of action
Little is known about the emergence and spatiotemporal spread of different fungicide resistant alleles belonging to different modes of action, such as methyl benzimidazole carbamates (MBCs), quinone outside inhibitors (QoIs) and succinate dehydrogenase inhibitors (SDHIs) fungicides [17], in this environment

Summary

Introduction

Airborne Aspergillus fumigatus (Af ) spores can, after inhalation, cause disease in animals and humans ranging from allergic conditions and chronic lung infection to acute invasive aspergillosis (IA). Patients with a weakened immune system are most at risk for IA, and successful therapy depends on early diagnosis and the effective use of antifungals. Due to their efficacy and low toxicity, orally administered azoles have been the drugs of choice, followed by intravenous applications of amphotericin B and echinocandins. Azole resistance has evolved in Af and is becoming more common in both the clinical setting and the wider environment since the late 1990s [1,2,3]. Further spread of resistance will have a significant clinical impact as higher mortality rates have already been recorded for patients with voriconazole-resistant IA in comparison with voriconazole-susceptible infection [4]. Further spread of resistance will have a significant clinical impact as higher mortality rates have already been recorded for patients with voriconazole-resistant IA in comparison with voriconazole-susceptible infection [4]. 4.0/).

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