Combined therapy against murine-disseminated infection by Fusarium verticillioides.

Using a murine model of disseminated infection by two strains of Fusarium verticillioides, we have evaluated the efficacy of high doses of amphotericin B (AMB) (3 mg/kg of body weight/day), voriconazole (VRC) (60 mg/kg of body weight/day), posaconazole (PSC) (100 mg/kg of body weight/day), and the combinations of AMB plus VRC or PSC. In general, our results were very modest. Neither combination was superior to the respective monotherapies. VRC alone and in combination with AMB was able to prolong survival but not to reduce tissue burden, and AMB plus PSC was able to reduce fungal load in organs but not to prolong survival.

Treatment of murine Fusarium verticillioides infection with liposomal amphotericin B plus terbinafine.

Using a murine model of disseminated infection by Fusarium verticillioides, the efficacy of liposomal amphotericin (L-AmB) B at 10mg/kg body weight once daily and terbinafine (TRB) at 150 mg/kg body weight twice daily, alone and in combination, was evaluated. The combination of L-AmB with TRB was the only treatment able to prolong survival and to reduce fungal loads in the spleen and kidneys of mice infected with either strain of F. verticillioides used. The results suggest that this combination may have a role in the treatment of F. verticillioides infection.

In vitro and in vivo antifungal susceptibilities of the Mucoralean fungus Cunninghamella.

We have determined the in vitro activities of amphotericin B (AMB), voriconazole, posaconazole (PSC), itraconazole (ITC), ravuconazole, terbinafine, and caspofungin against five strains of Cunninghamella bertholletiae and four of Cunninghamella echinulata. The best activity was shown by terbinafine against both species (MIC range = 0.3 to 0.6 µg/ml) and PSC against Cunninghamella bertholletiae (MIC = 0.5 µg/ml). We have also evaluated the efficacies of PSC, ITC, and AMB in neutropenic and diabetic murine models of disseminated infection by Cunninghamella bertholletiae. PSC at 40, 60, or 80 mg/kg of body weight/day was as effective as AMB at 0.8 mg/kg/day in prolonging survival and reducing the fungal tissue burden in neutropenic mice. PSC at 80 mg/kg/day was more effective than AMB at 0.8 mg/kg/day in reducing the fungal load in brain and lung of diabetic mice. Histological studies revealed an absence of fungal elements in organs of mice treated with either AMB at 0.8 mg/kg/day or PSC at 60 or 80 mg/kg/day in both models. ITC showed limited efficacy in both models. PSC could be a therapeutic option for the treatment of systemic infections caused by Cunninghamella bertholletiae.

Development of murine models of disseminated infection by Neoscytalidium dimidiatum.

We have developed two murine models of disseminated infections by Neoscytalidium dimidiatum, an emerging dematiaceous fungus. Immunosuppressed mice were challenged through the lateral tail vein with 1 x 10(5) or 1 x 10(6) CFU/ml and immunocompetent animals with 1 x 10(6) or 1 x 10(7) CFU/ml. N. dimidiatum var. dimidiatum was more virulent than the nonpigmented variety, N. dimidiatum var. hyalinum. All mice infected with N. dimidiatum var. dimidiatum died within 8 days while those infected with N. dimidiatum var. hyalinum survived to the end of the experiment. Fungal load in tissue was also higher in animals inoculated with N. dimidiatum var. dimidiatum. In general, of the five organs tested, spleens and kidneys were most affected.

Evaluation of antifungal therapy in a neutropenic murine model of Neoscytalidium dimidiatum infection.

We evaluated the efficacy of amphotericin B (1.5mg/kg/day), voriconazole (60mg/kg/day) and posaconazole (60mg/kg/day) in a murine model of systemic infection caused by Neoscytalidium dimidiatum. All the treatments were able to prolong survival and to reduce the tissue burden in the spleen and kidneys of infected mice. Neither voriconazole nor posaconazole improved the results achieved with amphotericin B.

Genotyping and in vitro antifungal susceptibility of Neoscytalidium dimidiatum isolates from different origins.

This study evaluated the genetic variability and in vitro susceptibility patterns of isolates of Neoscytalidium dimidiatum and Scytalidium hyalinum from different geographical origins. Partial sequences of four loci (the ITS region and D1/D2 domains of the 28S rRNA gene and the tubulin and chitin synthase genes) were analysed. Among a total of 1970 bp sequenced in 24 isolates, 7 polymorphic positions (0.36%) were detected, representing five different sequence types (ST1-ST5), from which two (ST2 and ST3) were detected exclusively in isolates from plants, two (ST1 and ST5) were found only in clinical isolates and one (ST4) was observed in isolates from humans and from a mango tree. We propose subordinating S. hyalinum as a variety of N. dimidiatum. Amphotericin B was the most active drug, but low minimum inhibitory concentrations were also detected for voriconazole, terbinafine and anidulafungin.

Interactions between triazoles and amphotericin B in treatment of disseminated murine infection by Fusarium oxysporum.

We have evaluated and compared the efficacies of high doses of amphotericin B (AMB; 3 mg/kg of body weight/day), voriconazole (60 mg/kg), and posaconazole (PSC; 100 mg/kg) alone and combined in a murine model of disseminated infection by Fusarium oxysporum. The combination of AMB with PSC showed the best results, prolonging the survival of mice and reducing their organ fungal loads. This combination might constitute a therapeutic option for those infections where monotherapies fail.

In vitro interactions of itraconazole and micafungin against clinically important filamentous fungi.

The in vitro interactions between itraconazole and micafungin against 133 strains of filamentous fungi of clinical interest were evaluated using a checkerboard method. Overall, synergistic interactions were observed against 30% of the strains tested. In the cases of Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Fonsecaea spp. and Sporothrix schenckii, synergistic interactions were observed against > or = 50% of the strains tested. For the rest of the fungi the interaction was indifferent; antagonism was not observed in any case.

Combined therapy in treatment of murine infection by Fusarium solani.

OBJECTIVES: We evaluated the efficacy of voriconazole, amphotericin B and micafungin alone and combined in a murine model of disseminated infection by Fusarium solani. METHODS: Immunosuppressed mice were treated with voriconazole at 60 mg/kg/day, amphotericin B at 3 mg/kg/day, micafungin at 10 mg/kg/day or combinations of these antifungal drugs. For survival studies, treatment began 1 day after infection and continued for 10 days. For tissue burden studies, animals were sacrificed on day 6 of the treatment and the fungal load in the kidneys and spleens was measured. The experiments were carried out using two different clinical strains of F. solani. RESULTS: Only the combination of voriconazole plus amphotericin B prolonged the survival of the mice versus the controls for the two strains tested. However, this combination only reduced tissue burden in the kidney and spleen of mice infected by one strain. The other treatments were clearly less effective. CONCLUSIONS: Voriconazole plus amphotericin B may have a role in the treatment of fusariosis.