Development of new strategies for the treatment of emerging opportunistic fungal infections

Identifier:  TDX:2449

Handle: https://hdl.handle.net/20.500.11797/TDX2449

Authors:  Martín Vicente, Adela

Abstract:
Aspergillus fumigatus is the most prevalent filamentous fungal pathogen and, although it is usually susceptible to antifungal drugs, resistant isolates have been detected recently. In addition, Neocosmospora solani, Lomentospora prolificans, Scopulariopsis brevicaulis and Scopulariopsis brumptii are some of the most important multiresistant fungi. Antifungal monotherapies usually fail, causing alarming mortality rates. For this reason, it is crucial to find alternative treatments and antifungal combinations could play an important role. In addition, Scedosporium apiospermum is an important neurotropic fungus for which the first line treatment is voriconazole. However, breakpoints are not available and the role of the susceptibility determination in cases of scedosporiosis is largely unknown. The main objectives of the thesis were to test the in vitro activity and in vivo efficacy of antifungal combinations against A. fumigatus and four species of multiresistant fungi; and to test the efficacy of voriconazole against S. apiospermum in a murine model in order to propose experimental tentative cutoffs. A good efficacy of the combinations of posaconazole with either amphotericin B or anidulafungin was observed against A. fumigatus, suggesting that these combinations can play an important role in case of refractory aspergillosis. Voriconazole showed efficacy in those S. apiospermum isolates with a MIC ≤ 2µg/ml and did not against the most resistant strain. Additionally, a good correlation between in vitro methods and in vivo outcome was found, suggesting that disk diffusion and Etest can be rapid alternatives for determining voriconazole susceptibility of S. apiospermum. In the case of the combinations against multiresistant fungi, the most synergistic combination was amphotericin B plus anidulafungin. The triple combination also showed a high percentage of synergism but this combination did not always show advantage over the double ones, suggesting that the administration of three drugs would not be better than two in some cases.