Identificador: TDX:484
Autores: Ortoneda Pedrola, Montserrat
Resumen:
Deep infections caused by moulds have increased during the last years, and especially those caused by opportunistic fungi. These fungi use to provoke infections in patients with underlying diseases such as leukaemia, AIDS, cancer, and solid organ or bone marrow transplant recipients. The number of fungal species involved in deep infections increases every day, and the strategies to treat these infections are still limited. The three genera of filamentous fungi that have been studied in the present thesis Fusarium, Scedosporium and Paecilomyces are included in the group of emerging opportunistic pathogens. Even though they just provoke severe infections in immunocompromised patients, the mortality rate is close to 100%. Amphotericin B has been for many years, and is still nowadays, the most used drug to treat the systemic infections, but it has important toxicity problems. In recent years newer formulations of the drug have been developed, which show less toxicity problems. The main objective of the present thesis has been to evaluate the efficacy of one of the newer formulations of amphotericin B, the liposomal preparation, in murine models of disseminated infection.To be able to compare both treatments we previously developed reproducible animal models of infection (using mice) that could simulate the human infection, for each one of the strains. This was in order to compare the efficacy of both formulations of amphotericin B, in the treatment of the infections caused by the studied fungi. This was evaluated by comparing using statistic methods the mean survival time of the different groups of mice (MST). We also compared the tissue burden of the fungi in several target organs of mice, which were sacrificed after the treatment. In addition to amphotericin B which is, as we said before, the most widely used drug to treat infections caused by opportunistic fungi, there are other antifungal agents, but they have shown low efficacy, at least in vitro, and the clinical results are very scarce. That is why we wanted to evaluate the possible synergic effect in vitro of some of these drug combinations.In a resumed way, the main conclusions derived from the several performed studies are as follows:1- We established murine models of disseminaded infection by the following species: Paecilomyces variotii, P. lilacinus, P. javanicus, Fusarium verticillioides, Scedosporium prolificans, and S. apiospermum in immunosuppressed or immunocompetent mice.2- We evaluated the efficacy of two formulations of the antifungal agent amphotericin B (the deoxycholate and the liposomal formulations) in the different experimental infection models developed in the first phase of the studies.In mice infected with P. variotii, both formulations showed similar results at low doses, but the administration of liposomal amphotericin B at 10 mg/kg provoked a significant decrease of the presence of the fungus in target organs.Low doses of liposomal amphotericin B increased the MST of mice infected with F. verticillioides. At high doses, it also lowered the presence of the fungus in several organs.In mice infected with S. prolificans, the administration of high doses of high doses of liposomal amphotericin B provoked an increase of MST, which was more evident with the highest dose. The administration of G-CSF together with the antifungal therapy did not improve the results. 3- We evaluated the in vitro activity of nine combinations of antifungal drugs against several species of the genera Fusarium and Paecilomyces.The combinations that showed a highest percentage of synergic effects for Fusarium were ravuconazole combined with amphotericin B or terbinafine, and terbinafine with voriconazole. The combinations that showed a highest percentage of synergic effects for Paecilomyces were terbinafine combined with any of the azoles.
Repositori URV