Human tissue distribution of caspofungin.

Tissue concentrations of caspofungin were determined in nine clinically relevant tissues taken during routine autopsy of 20 patients who had died during caspofungin treatment or within 23 days of cessation. The highest levels were achieved in liver, with concentrations ranging from ≤0.50 to 91.5 µg/g (0.60 µg/g 21 days after the last administration), followed by spleen (<0.25-46.3 µg/g), kidney (<0.25-33.6 µg/g) and lung (<0.25-31.0 µg/g). Intermediate concentrations were found in pancreas, skeletal muscle, thyroid and myocardium. The lowest concentrations were found in brain; caspofungin was only detectable in six of 17 samples. Caspofungin concentrations exceeded the minimum inhibitory concentration values of pathogenic Candida spp. in most of the tissue samples taken from patients who had died during treatment, except in brain samples. These findings warrant clinical outcome studies to establish the optimal treatment for deep-seated candidiasis, and support the current recommendations against echinocandins for treatment of fungal meningoencephalitis.

Comparison of Antimycotic Activity of Originator and Generics of Voriconazole and Anidulafungin against Clinical Isolates of Candida albicans and Candida glabrata.

BACKGROUND: Concerns have been expressed about the interchangeability of innovator and generic antifungals in their activity and chemical stability. MATERIALS/METHODS: The activity of two different antimycotics was tested, each with one originator and two generics. For voriconazole, the originator VFEND® (Pfizer) and the generics (Ratiopharm and Stada) were used for susceptibility testing (21 clinical isolates of Candida albicans (C. albicans); ATCC-90028 C. albicans) in RPMI growth media in compliance with the EUCAST criteria. Likewise, for anidulafungin, the originator ECALTA® (Pfizer) and the generics (Stada and Pharmore) were used for testing (20 clinical isolates of Candida glabrata (C. glabrata); ATCC-22019 Candida parapsilosis (C. parapsilosis)). Time Kill Curves (TKC) with concentrations above and below the respective MIC were performed for one strain for each antifungal. Stability testing of the antimycotics stored at 4 °C and at room temperature over 24 h was done, and samples were subsequently analyzed with HPLC. RESULTS: MIC results showed no significant difference in activity of generic and innovator antimycotic in all settings, which was also confirmed by TKC. Stability testing revealed no differences between originator and generic drugs. CONCLUSIONS: The present study demonstrates the interchangeability of generic and originator antimycotic in-vitro, potentially leading to broader public acceptance for generic antimycotics.

Human Tissue Distribution of Anidulafungin and Micafungin.

Concentrations of anidulafungin and micafungin were determined in eight different tissues obtained during autopsy of four deceased individuals who had been treated with anidulafungin and of seven who had received micafungin. The largest amounts were recovered from liver, with anidulafungin concentrations of 11.01 to 66.50 µg/g and micafungin levels of 0.36 to 5.53 µg/g (0.65 µg/g 30 days after the last administration). The lowest anidulafungin levels were measured in skeletal muscle, and the lowest micafungin concentrations were in kidneys.

Penetration of echinocandins into wound secretion of critically ill patients.

PURPOSE: Wound infections caused by Candida are life-threatening and difficult to treat. Echinocandins are highly effective against Candida species and recommended for treatment of invasive candidiasis. As penetration of echinocandins into wounds is largely unknown, we measured the concentrations of the echinocandins anidulafungin (AFG), micafungin (MFG), and caspofungin (CAS) in wound secretion (WS) and in plasma of critically ill patients. METHODS: We included critically ill adults with an indwelling wound drainage or undergoing vacuum-assisted closure therapy, who were treated with an echinocandin for suspected or proven invasive fungal infection. Concentrations were measured by liquid chromatography with UV (AFG and MFG) or tandem mass spectrometry detection (CAS). RESULTS: Twenty-one patients were enrolled. From eight patients, serial WS samples and simultaneous plasma samples were obtained within a dosage interval. AFG concentrations in WS amounted to < 0.025-2.25 mg/L, MFG concentrations were 0.025-2.53 mg/L, and CAS achieved concentrations of 0.18-4.04 mg/L. Concentrations in WS were significantly lower than the simultaneous plasma concentrations and below the MIC values of some relevant pathogens. CONCLUSION: Echinocandin penetration into WS displays a high inter-individual variability. In WS of some of the patients, concentrations may be sub-therapeutic. However, the relevance of sub-therapeutic concentrations is unknown as no correlation has been established between concentration data and clinical outcome. Nevertheless, in the absence of clinical outcome studies, our data do not support the use of echinocandins at standard doses for the treatment of fungal wound infections, but underline the pivotal role of surgical debridement.

Anidulafungin and Micafungin Concentrations in Cerebrospinal Fluid and in Cerebral Cortex.

Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin levels (<0.01 to 0.66 µg/ml) and micafungin levels (<0.01 to 0.16 µg/ml) were lower than those in plasma concentrations (0.77 to 5.07 and 1.21 to 8.70 µg/ml, respectively) drawn simultaneously. In cerebral cortex, anidulafungin and micafungin levels were 0.21 to 2.34 and 0.18 to 2.88 µg/g, respectively. Thus, MIC values of several pathogenic Candida strains exceed concentrations in CSF and in brain.

Adipocyte-specific inactivation of Acyl-CoA synthetase fatty acid transport protein 4 (Fatp4) in mice causes adipose hypertrophy and alterations in metabolism of complex lipids under high fat diet.

Fatp4 exhibits acyl-CoA synthetase activity and is thereby able to catalyze the activation of fatty acids for further metabolism. However, its actual function in most tissues remains unresolved, and its role in cellular fatty acid uptake is still controversial. To characterize Fatp4 functions in adipocytes in vivo, we generated a mouse line with adipocyte-specific inactivation of the Fatp4 gene (Fatp4(A-/-)). Under standard conditions mutant mice showed no phenotypical aberrance. Uptake of radiolabeled palmitic and lignoceric acid into adipose tissue of Fatp4(A-/-) mice was unchanged. When exposed to a diet enriched in long chain fatty acids, Fatp4(A-/-) mice gained more body weight compared with control mice, although they were not consuming more food. Pronounced obesity was accompanied by a thicker layer of subcutaneous fat and greater adipocyte circumference, although expression of genes involved in de novo lipogenesis was not changed. However, the increase in total fat mass was contrasted by a significant decrease in various phospholipids, sphingomyelin, and cholesteryl esters in adipocytes. Livers of Fatp4-deficient animals under a high fat diet exhibited a higher degree of fatty degeneration. Nonetheless, no evidence for changes in insulin sensitivity and adipose inflammation was found. In summary, the results of this study confirm that Fatp4 is not crucial for fatty acid uptake into adipocytes. Instead, under the condition of a diet enriched in long chain fatty acids, adipocyte-specific Fatp4 deficiency results in adipose hypertrophy and profound alterations in the metabolism of complex lipids.

Combination of enoxaparin and fibroblast growth factor-1 increases myocardial blood flow and capillary density after myocardial infarction in rabbits.

OBJECTIVE: The effect of enoxaparin and fibroblast growth factor-1 (FGF-1) on post-infarction capillary density and regional myocardial blood flow (RMBF) was examined. METHODS: New Zealand White rabbits received an intramyocardial injection of either physiological saline, FGF-1 + enoxaparin, FGF-1 or enoxaparin directly after ligation of the left anterior descending artery. RMBF and capillary density were investigated using fluorescent microspheres and histological examination. RESULTS: One week after infarction a significant difference in the number of capillaries could be demonstrated within the FGF-1 + enoxaparin group (p < 0.001 versus the control group), the FGF-1 group (p < 0.01) and the enoxaparin group (p < 0.05). Treatment with FGF-1 + enoxaparin resulted in a significantly increased number of capillaries compared to treatment with FGF-1 (p < 0.05) and enoxaparin (p < 0.05) alone. Additionally, all groups treated with FGF-1 and/or enoxaparin showed a significant increase of microvessel density in the treated ischemic border zone compared to the non-treated ischemic border zone (p < 0.001 for FGF-1 + enoxaparin, p < 0.01 for FGF-1, p < 0.05 for enoxaparin). RMBF was significantly increased within the FGF-1 + enoxaparin group compared to the control group (p < 0.05). Moreover, perfusion rates within the FGF-1 + enoxaparin-treated area did not significantly differ from the pre-infarction values. CONCLUSION: Treatment with either enoxaparin or FGF-1 or FGF-1 + enoxaparin resulted in increased microvessel growth. However, only the combination of enoxaparin with FGF-1 promotes capillary growth and RMBF. Thus, we conclude that enoxaparin enhances the angiogenic potential of intramyocardially injected FGF-1 in the acutely infarcted rabbit heart.