TY - JOUR
T1 - Antifungal activity of posaconazole and granulocyte colony-stimulating factor in the treatment of disseminated zygomycosis (mucormycosis) in a neutropaenic murine model
AU - Saoulidis, Stamatis
AU - Simitsopoulou, Maria
AU - Dalakiouridou, Maria
AU - Walsh, Thomas J.
AU - Wheat, L. Joseph
AU - Papaioannidou, Paraskevi
AU - Roilides, Emmanuel
PY - 2011/9
Y1 - 2011/9
N2 - The aim of this study was to evaluate the pharmacokinetics and efficacy of posaconazole (PSC) in combination with granulocyte colony-stimulating factor (G-CSF) in a neutropaenic murine model of disseminated zygomycosis (mucormycosis) due to Rhizopus microsporus. Male BALB/c mice were rendered neutropaenic with cyclophosphamide (200mgkg -1, intraperitoneally) administered on days -1 and +5 postinfection. Mice were infected with R. microsporus (5×10 4 sporesml -1) intravenously. Mice were treated with PSC (40mgkg -1day -1 by gavage) or G-CSF (300μgkg -1day -1 subcutaneously) or with the combination of PSC and G-CSF. The fungal burden was assessed by culturing the brain, liver, kidneys and lungs. Blood levels of PSC were measured by high performance liquid chromatography. The survival rates were 33%, 27% and 31% for PSC-treated-, G-CSF-treated- and PSC+G-CSF-treated mice, respectively, as compared to 18% for the controls (P=NS). PSC monotherapy and combination therapy significantly reduced the fungal burden in the kidneys, but not in the rest of the organs. Combination therapy was not superior to PSC monotherapy in terms of either survival or reduction in fungal burden. Serum concentrations of PSC were well-above the MIC of PSC for the particular isolate. PSC monotherapy has a modest efficacy against R. microsporus in reducing fungal burden in neutropaenic mice. Combining G-CSF with PSC does not substantially affect the antifungal activity of PSC.
AB - The aim of this study was to evaluate the pharmacokinetics and efficacy of posaconazole (PSC) in combination with granulocyte colony-stimulating factor (G-CSF) in a neutropaenic murine model of disseminated zygomycosis (mucormycosis) due to Rhizopus microsporus. Male BALB/c mice were rendered neutropaenic with cyclophosphamide (200mgkg -1, intraperitoneally) administered on days -1 and +5 postinfection. Mice were infected with R. microsporus (5×10 4 sporesml -1) intravenously. Mice were treated with PSC (40mgkg -1day -1 by gavage) or G-CSF (300μgkg -1day -1 subcutaneously) or with the combination of PSC and G-CSF. The fungal burden was assessed by culturing the brain, liver, kidneys and lungs. Blood levels of PSC were measured by high performance liquid chromatography. The survival rates were 33%, 27% and 31% for PSC-treated-, G-CSF-treated- and PSC+G-CSF-treated mice, respectively, as compared to 18% for the controls (P=NS). PSC monotherapy and combination therapy significantly reduced the fungal burden in the kidneys, but not in the rest of the organs. Combination therapy was not superior to PSC monotherapy in terms of either survival or reduction in fungal burden. Serum concentrations of PSC were well-above the MIC of PSC for the particular isolate. PSC monotherapy has a modest efficacy against R. microsporus in reducing fungal burden in neutropaenic mice. Combining G-CSF with PSC does not substantially affect the antifungal activity of PSC.
KW - Antifungal therapy
KW - Azoles
KW - Cytokines
KW - Murine mucormycosis
KW - Murine zygomycosis
KW - Rhizopus microsporus
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UR - http://www.scopus.com/inward/citedby.url?scp=79955065836&partnerID=8YFLogxK
U2 - 10.1111/j.1439-0507.2010.01958.x
DO - 10.1111/j.1439-0507.2010.01958.x
M3 - Article
C2 - 21039940
AN - SCOPUS:79955065836
SN - 0933-7407
VL - 54
SP - e486-e492
JO - Mycoses
JF - Mycoses
IS - 5
ER -