Aspergillus fumigatus is a widespread fungal species found in the environment. It is not only a plant pathogen but also an important pathogen to humans. While a variety of antifungal agents are available to treat Aspergillus diseases in agriculture, a more restricted panel of antifungal agents are available for the treatment of A. fumigatus infections in humans. Some of the antifungal classes used in medicine are also used largely in agriculture. With the rise in infections due to A. fumigatus in humans and the increasing use of antifungal agents, cases of antifungal resistance have been reported and are expected to occur more frequently. There are no systematic studies which investigated the incidence of antifungal resistance in A. fumigatus isolates sampled in the environment and from patients in swiss hospitals. This study is aimed to determine the current situation of antifungal resistance in this important pathogen and to gain information on the cellular mechanisms responsible for antifungal resistance.
Background
Aspergillus fumigatus is the commonest mould causing infection worldwide. The frequency of invasive aspergillosis has risen for example 14-fold over the 12 years up to 1992. Currently, invasive aspergillosis accounts for 4% of all deaths in tertiary care hospitals in Europe as compared with about 2% for invasive candidiasis. Patients at risk include those undergoing organ transplants or being neutropenic by cancer treatments. The crude mortality from invasive aspergillosis is around 85% and falls to around 50% if antifungal treatment is given. A. fumigatus is found widespread in the environment through dispersion by small spore. It is a common mould found in composts and has an important role in the degradation of almost all components in organic waste.
Due to the augmentation of A. fumigatus infections in humans, the need for antifungal agents to treat these diseases has increased in the past years. In humans, the class of azole antifungal agents (for example itraconazole and the newly introduced voriconazole) and polyenes (for example amphotericin B) are the most frequent antifungal agents used to treat A. fumigatus infections. Both agents target specific steps in the ergosterol biosynthetic pathway. In crop protection, fungicides have become an integral part of efficient food production. Although azoles were discovered and developed to fight human fungal disease, similar compounds are available in crop protection. Several other fungicides are used to combat fungal infections in the environment but are not used in medicine because of their toxicity. The use of antifungal agents in humans or in the environment carries the potential problems of development of resistance in fungal species. As far as A. fumigatus is concerned, antifungal treatments aimed to cure this fungal species in patients are often not successful. This clinical resistance correlates with recent studies demonstrating the isolation of A. fumigatus strains being less susceptible in vitro to agents such as itraconazole. Antifungal susceptibility testing showed that 6% of UK isolates of A.fumigatus are resistant to itraconazole. Itraconazole resistance has now been documented in several other countries. Mechanisms responsible for the development of antifungal resistance are still poorly understood in A. fumigatus.
Aim
A. fumigatus infections are life-threatening in humans and their incidence is increasing in hospitals. Either in hospitals or in the environment, A.fumigatus will be under the pressure of increasing antifungal treatments and emergence of resistance is expected. No detailed analysis exists on the degree of antifungal resistance in strains isolated from the environment or from hospital site in Switzerland. Mechanisms responsible for the development of antifungal resistance are still poorly understood in A. fumigatus. A better comprehension of these mechanisms will not only be vital for the design of new antifungal drugs to combat these life-threatening infections, but also will allow to develop tools enabling the rapid detection of resistance in fungal population of different origins. The present research proposal is therefore aimed:
1) To collect A. fumigatus isolates from patients, animals, food and environment (compost) and to test their susceptibility to different antifungals in order to detect possible resistant strains
2) To clone A. fumigatus genes involved in antifungal drug resistance
3) To investigate if the cloned genes participate in the development of resistance in sampled isolates
Significance
Very few studies have been undertaken to elucidate the mechanisms of resistance to antifungal drugs in A. fumigatus Due to the increasing importance of A. fumigatus infections coupled with the high mortality and to the restricted number of effective agents, it is essential to explore how a fungal pathogen can circumvent their effects by cellular and genetic alterations. Acquisition of knowledge in this field is required for the design of novel antifungal drugs. Little is known also on the impact of environmental factors on the fate of antifungal drug resistance in fungal pathogens. A. fumigatus is especially interesting in this respect because the same pathogen is causing life-threatening diseases in humans and is also widely distributed in the environment.
