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Antifungal activity of posaconazole and granulocyte colony-stimulating factor in the treatment of disseminated zygomycosis (mucormycosis) in a neutropaenic murine model.

Abstract
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 (200 mg kg(-1), intraperitoneally) administered on days -1 and +5 postinfection. Mice were infected with R. microsporus (5 × 10(4) spores ml(-1)) intravenously. Mice were treated with PSC (40 mg kg(-1) day(-1) by gavage) or G-CSF (300 μg kg(-1) day(-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.
AuthorsStamatis Saoulidis, Maria Simitsopoulou, Maria Dalakiouridou, Thomas J Walsh, L Joseph Wheat, Paraskevi Papaioannidou, Emmanuel Roilides
JournalMycoses (Mycoses) Vol. 54 Issue 5 Pg. e486-92 (Sep 2011) ISSN: 1439-0507 [Electronic] Germany
PMID21039940 (Publication Type: Journal Article)
Copyright© 2010 Blackwell Verlag GmbH.
Chemical References
  • Triazoles
  • Granulocyte Colony-Stimulating Factor
  • posaconazole
Topics
  • Animal Structures (microbiology)
  • Animals
  • Colony Count, Microbial
  • Disease Models, Animal
  • Granulocyte Colony-Stimulating Factor (administration & dosage, pharmacokinetics)
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neutropenia (complications)
  • Rhizopus (drug effects, isolation & purification)
  • Rodent Diseases (drug therapy)
  • Treatment Outcome
  • Triazoles (administration & dosage, pharmacokinetics)
  • Zygomycosis (drug therapy)

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