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Fusarium solani infections are notoriously difficult to treat. We compared the efficacy of polyenes and an echinocandin in treating murine fusariosis to identify the optimal therapeutic regimen.Neutropenic mice infected intravenously with F. solani were treated with amphotericin B (AmB), liposomal AmB (LAmB), amphotericin B lipid complex (ABLC), caspofungin acetate or a combination of LAmB and caspofungin. Treatment was initiated prior to infection (prophylactic therapy), 24 h post-infection (delayed therapy) or 2 days before infection and continued for 1 day after (continuous therapy).Prophylaxis only with LAmB significantly reduced brain or kidney fungal burden compared with placebo. No prophylactic treatment improved survival. LAmB levels in the kidneys were higher than ABLC or AmB levels, which were often undetectable. In the delayed therapy model, neither polyenes nor caspofungin improved survival. In the continuous therapy model, LAmB or LAmB plus caspofungin did not improve survival even though they did decrease fungal burden. In contrast, continuous caspofungin at 1 but not 5 mg/kg/day improved survival, but did not decrease fungal burden. Kidney inflammation and tissue necrosis were markedly decreased in mice treated with caspofungin compared with other treatments.These studies demonstrate a dissociation between survival and tissue fungal burden during murine fusariosis. Although prophylactic LAmB may be useful at reducing tissue fungal burden, polyenes had limited survival benefit for active fusariosis. Caspofungin at 1 but not 5 mg/kg/day mediated surprising improvements in survival during active fusariosis, despite lack of reduction in fungal burden. Further studies are warranted.