Antifungal drug resistance caused by agricultural use of azoles?

Submitted by Aspergillus Administrator on 1 December 2009

Azole antifungals (itraconazole, voriconazole, posaconazole) are depended on in medical clinics to treat fungal infections. They are effective but the nature of the infection often means that the patients has to take the medication for long periods of time. Improvement is usually achieved but after a while progress can slow and it is often found that a strain of the fungus has grown out which is resistant to that antifungal drug.

Fungi can develop resistance to antifungal drugs naturally over time but it is a rare event and once it happens there is no know mechanism for the fungus to transfer the resistance genes to other fungi – something that is common in bacteria. This limits the frequency of resistance arising anew in fungi.

Where does the resistance come from? For resistant strains to multiply the fungus must come into contact with antifungals and thus encourage resistant strains grow out. Apart from in a patient undergoing antifungal treatment where does that happen? A recent paper (Science 326:1173 (2009)) strongly suggests that one place that this happens is when crops are treated with antifungal azoles in order to prevent fungal spoilage. Antifungal azoles are known to be used on a very large scale on orchards, vineyards and some grain crops in europe so this would be a good place for resistance to emerge.

Spores from strains of Aspergillus that are resistant to some antifungals have been found close to Radboud University Nijmegen Medical Centre in the Netherlands suggesting that they could be breathed in by patients. The type of mutation found in fungi that infected patients was also found in most of the fungi isolated outside the hospital in soils. This adds up to a strong possibility that those patients breathed in fungi that were already resistant to the antifungals used in the clinic when they were breathed in. 94% of the clinical isolates at Nijmegen and 69% at other Dutch centres carried the same mutation, suggesting a single event or single cause of the resistance found.

The situation in Radboud University Nijmegen Medical Centre seems to be different to that in the National Aspergillosis Centre Manchester, UK as in Manchester there was a range of different mutations in strains which suggested that there were several different original events that caused those mutations.

The true situation is still not completely clear and the results found in the Netherlands might not be representative of the pattern of resistance everywhere but as the original paper states, this is enough to require us to think carefully about allowing the large scale use of azoles in agriculture.