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

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.

Amphotericin B formulations variably enhance antifungal activity of human neutrophils and monocytes against Fusarium solani: comparison with Aspergillus fumigatus.

OBJECTIVES: Lipid formulations of amphotericin B (AMBF) are widely used in the treatment of life-threatening infections caused by Aspergillus fumigatus and Fusarium solani. We aimed to compare the immunomodulatory effects of four AMBF, deoxycholate (DAMB), liposomal (LAMB), lipid complex (ABLC) and colloidal dispersion (ABCD), on the oxidative antifungal activities of human neutrophils (PMNs) and monocytes (MNCs) against hyphae of A. fumigatus and F. solani. METHODS: Human PMNs and MNCs were pre-incubated with 1 or 5 mg/L DAMB and 5 or 25 mg/L for each of LAMB, ABLC and ABCD. Hyphal damage was then assessed by XTT assay, and O2- production was assessed by cytochrome c assay. RESULTS: All agents resulted in increased hyphal damage induced by phagocytes against both A. fumigatus and F. solani (P < 0.05). The high concentrations of AMBF elicited higher phagocyte-induced hyphal damage of both fungi than the low concentrations. There was, however, no consistent superiority of any of the AMBF or substantial effector cell:target ratio-dependent differences in the degree of hyphal damage enhancement. By comparison, O2- produced by PMNs or MNCs upon hyphal challenge was not generally affected by any of the AMBF. F. solani hyphae were significantly more resistant to H2O2 than A. fumigatus. CONCLUSIONS: These findings suggest that AMBF have enhancing effects of variable degree on phagocyte-induced hyphal damage of A. fumigatus and F. solani. Other fungicidal mechanisms, perhaps non-oxidative, are more likely to mediate these immunomodulatory effects of AMBF on host defence against the two medically important filamentous fungi.

Differential activities of newer antifungal agents against Candida albicans and Candida parapsilosis biofilms.

The activities of voriconazole, posaconazole, caspofungin, and anidulafungin against Candida albicans and Candida parapsilosis biofilms were evaluated. In contrast to planktonic cells, the MICs for voriconazole and posaconazole for the biofilms of the two species were high (>or=256 and >64 mg/liter, respectively) but relatively low for the echinocandins caspofungin and anidulafungin (

The association between male infertility and sperm disomy: evidence for variation in disomy levels among individuals and a correlation between particular semen parameters and disomy of specific chromosome pairs.

BACKGROUND: The association between infertility and sperm disomy is well documented. Results vary but most report that men with severely compromised semen parameters have a significantly elevated proportion of disomic sperm. The relationship between individual semen parameters and segregation of specific chromosome pairs is however less well reported as is the variation of disomy levels in individual men. METHODS: In order to address these questions the technique of fluorescent in-situ hybridisation (FISH) was utilised to determine the disomy levels of chromosomes X, Y and 21 in 43 sperm samples from 19 infertile males. The results generated from this study were analysed using logistic regression. RESULTS: In this study we compared levels of sperm concentration, motility and morphology with levels of sperm disomy for chromosome 21 and the sex chromosomes. Our results suggest that there is considerable variation in disomy levels for certain men. They also suggest that oligozoospermic males have significantly elevated levels of sex chromosome disomy but not disomy 21; they suggest that severe asthenozoospermic males have significantly elevated levels of disomy 21 but not sex chromosome disomy. Surprisingly, severe teratozoopsermic males appeared to have significantly lower levels of sperm disomy for both the sex chromosomes and chromosome 21. CONCLUSION: We suggest that the association between sex chromosome disomy and oligozoospermia may be due to reduced recombination in the XY pairing region and discuss the relevance of our findings for the correlations between sperm disomy and sperm motility and morphology.