2024-02-25 16:27:16
What is the relationship between tulip bulbs and aspergillosis, a serious disease caused by a microscopic fungus, mold Aspergillus fumigatus ? This is what we tried to discover at the University Hospital Center (CHU) of Besançon.
Over the past twenty years, the number of clinical cases of aspergillosis due to strains ofAspergillus resistant to the most used antifungals is increasing. However, these same antifungals are also used in agriculture and horticulture.
We wondered whether planting tulip bulbs treated with antifungals in hospitals could facilitate the emergence of resistant strains transmissible to humans.
The results we obtained suggest that the use of such bulbs could indeed promote the development of resistance to antifungals.
These results particularly raise questions in the current context of suspension of the Écophyto plan, the objective of which was to reduce the use of pesticides and fungicides in agriculture…
Invasive aspergillosis, a fatal opportunistic disease
Aspergillosis is a disease caused by microscopic fungi (mold) of the genus Aspergillus. It can manifest in the form of localized infections, fatal disseminated infection or allergic diseases, and affect many organs (kidneys, sinuses, skin, blood, etc.).
In France, it is the third cause of invasive fungal infection. Mainly caused by Aspergillus fumigatusaspergillosis affects immunocompromised people, in particular patients who have received a bone marrow or organ transplant, as well as patients undergoing anticancer treatments.
The spores ofAspergillus fumigatus are omnipresent in the air, in the soil, on agricultural plants, and in compost. Therefore, inhalation of these spores is inevitable. Normally, this is not a problem, because the spores are eliminated by the immune defenses in the respiratory system.
A preparation of the microscopic fungus Aspergillus fumigatus, seen under a 40x magnifying lens. S. Rocchi, Provided by the author
However, in certain people, aspergillosis is a so-called “opportunistic” disease: when the immune system is deficient (immunosuppression), the fungus contaminates the lungs and can develop there, and by extension cause invasive aspergillosis (and colonization of other organs).
From 2012 to 2018, 1,661 cases of this disease were recorded in our country, with a mortality rate of 42.5% among patients who also had a blood disease, who represented 60% of cases of invasive aspergillosis.
Emergence of drug-resistant strains
Treatment of aspergillosis requires the use of antifungal medications. Azoles work by blocking the production of an important component of the cell membrane of fungi, ergosterol. These are therapies that combine effectiveness and good tolerance for patients.
These are used to treat not only human beings but also animals. Furthermore, they are also widely used as fungicides in agriculture (fields, market gardening, viticulture), in sawmills and in horticulture, in order to fight against fungi which attack plants (phytopathogens) or wood (lignivores). .
However, when azole fungicides are applied in the environment, they have an unintended impact on Aspergillus : they eliminate sensitive strains and favor, through selection pressure, those which have adapted to these azole molecules. Result: strains insensitive to azole fungicides develop.
The escalation of the quantities of widespread antifungals and the use of mixtures of antifungals have not made it possible to stem the appearance of this resistance. Nor even, moreover, to sustainably eradicate phytopathogens from rice, wheat, corn, soya and potato crops.
On the other hand, now many patients with aspergillosis are infected with such a strain ofAspergillus resistant to azoles. However, there are few alternative treatments, some being ineffective against so-called “filamentous” species such as Aspergillus or toxic for certain patients (amphotericin is for example more effective, but potentially toxic for the kidneys).
One of the possible measures to avoid these resistant fungal infections in the short term is the prevention of exposure.
Screen for azole-resistant strains
With a view to better preventing infections by strains ofAspergillus fumigatus resistant to azoles, since 2015, we have been carrying out their screening in indoor air at the University Hospital Center of Besançon.
Because research had suggested that azole-treated ornamental plant bulbs could play a role in the global spread of the strains, we extended our environmental monitoring to include soil sampling. We therefore wanted to assess whether the terrace of our hospital, decorated with flower pots, could be a potential source of the spread of resistance.
In 2019, a total of 69 isolates fromAspergillus fumigatus resistant to azoles, and presenting a TR34/L98H mutation, having been described as linked to the use of fungicides in the environment, were obtained: 1 from the air of the intensive care unit, 4 from from the main corridors of the hospital, 59 from tulip pots imported from the Netherlands and 5 from the soil of trees grown in pots.
Confirming the hypothesis that the resistant strains collected in hospital corridors or isolated in clinical samples actually came from treated bulbs planted in flower beds would still require sequencing their genome. But in any case, these results showed the interest in better monitoring the potential sources of emergence of resistance in our hospital.
Say it with flowers instead… organic
Following these results, and the increased risk of nosocomial infections (infections contracted in hospital), it was decided to no longer plant treated bulbs.
In order not to radically eliminate the existence of terraces with tulip planters, to preserve a place for patients to walk, we recommended the replacement of treated tulip bulbs with bulbs from organic horticulture, without requiring the change. of the earth.
The tulip beds located in front of the entrance to the Besançon University Hospital. S. Rocchi, Provided by the author
A year later we took the same samples from the earthen tanks, with the same procedure. We found that the resistance rate fell from 71% to less than 3% in one year. These results suggest that replacing treated bulbs with organic bulbs may be sufficient to reestablish a predominantly susceptible population in just one year.
Need for environmental monitoring
So far, Aspergillus fumigatus has been little studied in the environment, because it is not a phytopathogenic fungus causing crop losses.
However, now genotypes ofAspergillus fumigatus Resistant to several azoles are detected worldwide, in clinical isolates as well as in the environment.
The widespread use of azole fungicides in the environment is a major factor in the selection of resistance to medical antifungals. It is therefore imperative to support the development of approaches that will ultimately disconnect the use of antifungals in agriculture and their use in the clinic.
Although it is attractive to suggest a rapid evolution towards sustainable agriculture without pesticides, or that certain classes of antifungals be reserved exclusively for clinical use, this does not seem feasible in the short term: the number of effective molecules available is low , and agriculture faces the same problem of resistance.
In such a situation, surveillance systems to track strains ofAspergillus fumigatus resistant to antifungals are essential. Unfortunately, there is a lack of such systems at present.
Furthermore, understanding of how resistance persists, evolves or can be managed remains incomplete. This knowledge gap seriously threatens the management of fungal diseases in humans and animals.
Protecting patients from the emergence of resistant strains linked to the use of new fungicides
The need for environmental monitoring has also become more pressing as five antifungal agents with novel modes of action are under development.
Among them, olorofim, a new antifungal from the orotomide class, represents hope for patients with resistant aspergillosis. This new drug already has a fungicide analogue recently approved by theU.S. Environmental Protection Agency. But research has shown that this molecule is capable of inducing resistance in vitro.
Similar to what happened with azole fungicides, the massive use of orotomide fungicides risks reducing treatment possibilities in patients with fungal infections.
European projects aim to develop a standardized method for environmental monitoring. Such a tool will improve the monitoring and understanding of resistance patterns and allow for the assessment of associations with work practices (spraying, composting), as well as the influence of other factors (geographic, climatic) on resistance levels. .
This may reduce exposure to Aspergillus fumigatus resistant to antifungals, which should make it possible to reduce the number of patients suffering from azole-resistant aspergillosis, and therefore significantly reduce mortality.
In the meantime, in hospital gardens, it is preferable for patient safety to use exclusively organic plants!
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