A fungicide in the field, resistance in the hospital

Aspergillus fumigatus lives in soil, compost and decaying plant matter, and everyone inhales its spores daily. In people with normal immunity that comes to nothing. In patients with severe neutropenia or after transplantation it can cause invasive aspergillosis with high mortality, treated with azoles.

The paper by Paul Verweij and colleagues, published in 2009 in The Lancet Infectious Diseases, described a phenomenon that had been building in the Netherlands since 1999: invasive aspergillosis caused by multi-azole-resistant strains. The proportion of patients harbouring resistant isolates ranged from 6.0 to 12.8 per cent.

The shape of the resistance was decisive. More than ninety per cent of resistant clinical isolates carried one and the same mechanism, denoted TR/L98H: a substitution at codon 98 of the cyp51A gene combined with a 34-base-pair tandem repeat in the promoter region. A single dominant mechanism does not look like resistance arising repeatedly and independently during treatment.

The rest of the evidence is environmental. TR/L98H strains were cultured from soil and compost, shown to be cross-resistant to azole agricultural fungicides, and found to be genetically related to resistant clinical isolates. Azoles are used abundantly in agriculture, so selection could have happened in the environment long before any contact with a patient.

That is exactly why this entry sits under Conservation rather than Medicine. The patient did nothing that produced their resistance — it arose in the landscape. The authors noted that reports of TR/L98H from other European countries suggested the phenomenon was already spreading.

The mechanism and prevalence need a date

The most common environmental variant is cyp51A TR34/L98H, not “TR/L98H.” Dutch evidence reported in 2009 found multi-azole-resistant Aspergillus fumigatus even in patients with no previous azole therapy; the 6.0–12.8% prevalence belongs to that setting and period, not to the world today. A 2025 joint EU-agency assessment concluded that non-medical azole use—especially in agriculture and horticulture—contributes to the risk of resistant Aspergillus. EU/EEA sales data covered 2010–2021, with plant-protection products the largest reported sector. This is a One Health pathway, not a simple trace from one field to one patient; the attributable share of individual uses and hotspots remains uncertain.