Therapies against murine Candida guilliermondii infection, relationship between in vitro antifungal pharmacodynamics and outcome / Terapia antifúngica frente a la infección por Candida guilliermondii en ratones, correlación entre los parámetros farmacodinámicos in vitro y la eficacia in vivo

Background. Candida guilliermondii has been recognized as an emerging pathogen showing a decreased susceptibility to fluconazole and considerably high echinocandin MICs. Aims. Evaluate the in vitro activity of anidulafungin in comparison to amphotericin B and fluconazole against different isolates of C. guilliermondii, and their efficacy in an immunosuppressed murine model of disseminated infection. Methods. The in vitro susceptibility of four strains against amphotericin B, fluconazole and anidulafungin was performed by using a reference broth microdilution method and time-kill curves. The in vivo efficacy was evaluated by determination of fungal load reduction in kidneys of infected animals receiving deoxycholate AMB at 0,8 mg/kg i.v., liposomal amphotericin B at 10 mg/kg i.v., fluconazole at 50 mg/kg, or anidulafungin at 10 mg/kg. Results. Amphotericin B and anidulafungin showed fungicidal activity, while fluconazole was fungistatic for all the strains. In the murine model, liposomal amphotericin B at 10 mg/kg/day was effective in reducing the tissue burden in kidneys of mice infected with any of the tested strains. However, amphotericin B, anidulafungin and fluconazole were only effective against those strains showing low MIC values. Conclusions. Liposomal amphotericin B showed the higher activity and efficacy against the two strains of C. guilliermondii, in contrast to the poor effect of fluconazole and anidulafungin. Further studies with more isolates of C. guilliermondii representing a wider range of MICs should be carried out to assess whether there is any relationship between MIC values and anidulafungin efficacy (AU)

Antecedentes. Candida guilliermondii es un patógeno emergente, con reducida sensibilidad al fluconazol y a las equinocandinas. Objetivos. Evaluar la actividad in vitro de la anidulafungina, en comparación con la de la anfotericina B y el fluconazol, frente a C. guilliermondii y su eficacia en un modelo animal de infección diseminada. Métodos. La sensibilidad in vitro se valoró mediante microdilución en caldo y curvas de mortalidad. La eficacia in vivo se evaluó mediante la determinación de la carga fúngica en riñón de ratones inmunosuprimidos con infección diseminada por C. guilliermondii tratados con anfotericina B desoxicolato (0.8 mg/kg i.v.), anfotericina B liposomal (10 mg/kg i.v.), fluconazol (50 mg/kg) o anidulafungina (10 mg/kg). Resultados. La anfotericina B y la anidulafungina mostraron actividad fungicida, mientras que el fluconazol fue fungistático frente a todas las cepas. En el modelo murino, la anfotericina B liposomal redujo para todas las cepas la carga fúngica en riñones, mientras que la anfotericina B desoxicolato, la anidulafungina y el fluconazol fueron efectivas solo en aquellos animales infectados con las cepas de menor valor de concentración mínima inhibitoria (CMI). Conclusiones. La anfotericina B liposomal mostró la mayor actividad y eficacia frente a C. guilliermondii, en contraste con el limitado efecto del fluconazol y de la anidulafungina. Se necesitan estudios que incluyan cepas con un rango más amplio de CMI que permitan determinar la relación entre la actividad in vitro y la eficacia de la anidulafungina (AU)

Therapies against murine Candida guilliermondii infection, relationship between in vitro antifungal pharmacodynamics and outcome.

BACKGROUND: Candida guilliermondii has been recognized as an emerging pathogen showing a decreased susceptibility to fluconazole and considerably high echinocandin MICs. AIMS: Evaluate the in vitro activity of anidulafungin in comparison to amphotericin B and fluconazole against different isolates of C. guilliermondii, and their efficacy in an immunosuppressed murine model of disseminated infection. METHODS: The in vitro susceptibility of four strains against amphotericin B, fluconazole and anidulafungin was performed by using a reference broth microdilution method and time-kill curves. The in vivo efficacy was evaluated by determination of fungal load reduction in kidneys of infected animals receiving deoxycholate AMB at 0,8 mg/kg i.v., liposomal amphotericin B at 10 mg/kg i.v., fluconazole at 50 mg/kg, or anidulafungin at 10 mg/kg. RESULTS: Amphotericin B and anidulafungin showed fungicidal activity, while fluconazole was fungistatic for all the strains. In the murine model, liposomal amphotericin B at 10 mg/kg/day was effective in reducing the tissue burden in kidneys of mice infected with any of the tested strains. However, amphotericin B, anidulafungin and fluconazole were only effective against those strains showing low MIC values. CONCLUSIONS: Liposomal amphotericin B showed the higher activity and efficacy against the two strains of C. guilliermondii, in contrast to the poor effect of fluconazole and anidulafungin. Further studies with more isolates of C. guilliermondii representing a wider range of MICs should be carried out to assess whether there is any relationship between MIC values and anidulafungin efficacy.

Experimental therapy with azoles against Candida guilliermondii.

We evaluated the in vitro killing activity of voriconazole (VRC) and posaconazole (PSC) against two clinical isolates of Candida guilliermondii. The two drugs showed fungistatic activity against both isolates and were effective in reducing kidney fungal burden in a neutropenic murine model of disseminated candidiasis in infected mice. PSC was significantly more effective than VRC against one of the strains. The serum levels of PSC and VRC were above the corresponding MICs for these isolates.

Effect of antifungal treatment in a murine model of blastoschizomycosis.

Blastoschizomyces capitatus is an emerging pathogenic fungus that can cause deep invasive diseases in neutropenic patients. We developed a model of disseminated blastoschizomycosis in immunosuppressed mice to evaluate the effectiveness of amphotericin B, flucytosine, fluconazole and voriconazole. High-dose fluconazole was the most effective drug at prolonging the survival of mice and at reducing fungal burden in the kidneys, spleen and liver.