Granulomatous Inflammation in the Lungs of Mice with Systemic Candidiasis Receiving a Composition of Amphotericin B and Dialdehyde Dextran

A composition of amphotericin B and dialdehyde dextran was used for the therapy of male C57Bl/6 mice with systemic candidiasis. The composition was more effective than free amphotericin B. A decrease in the number and size of candidal granulomas in the lungs was more significant after therapy with the study composition (compared to free amphotericin B). Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 80–82, 2008     

Structural Changes in the Liver and Content of Steroid Hormones in the Blood and Adrenal Glands of Mice with Systemic Candidiasis Treated with A Composition of Amphotericin B and Dialdehyde Dextran

In CBA mice infected with C. albicans, phasic pattern of granulomatosis development was observed. In all groups, the number of granulomas in the liver was minimum on day 56 after infection. Treatment with free amphotericin B and its composition with dialdehyde dextran (CA) reduced the number of infiltrations and granulomas in the liver, the changes were more pronounced in animals receiving CA. A different pattern of cyclic fluctuations of cortisol content in the blood and adrenal glands and progesterone content in the adrenal gland was observed. By the end of observation (day 84), cortisol content in the blood and adrenals of mice treated with CA was considerably lower than in untreated mice and animals receiving amphotericin B. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 16–19, 2008     

Effects of modified amphotericin in experimental systemic candidiasis

Lysosomotropic composition of dialdehyde dextran and amphotericin B had a greater therapeutic effect in mice with systemic candidiasis compared to free amphotericin B. This composition normalized glucocorticoid function of the adrenal glands and decreased the severity of liver destruction at late terms of granulomatous inflammation. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 4, pp. 367–369, April, 2007     

Effect of Lysosomotropic Form of Amphotericin B on Functional State of Phagocytes in Experimental Candidiasis

Effect of antifungal preparation amphotericin B and its lysosomotropic composition with dialdehyde-dextran on functional state of phagocytizing cells in the dynamics of granulomatous inflammation induced by C. albicans was studied on CBA mice. A stimulating effect of amphotericin B on the production of reactive oxygen species by peritoneal and bone marrow phagocytes was observed, while lysosomotropic form of the antibiotic did not stimulate generation of oxygen radicals. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 13–15, 2008     

Therapeutic Efficacy and Hepatotoxicity of a Composition of Isoniazid and Dialdehyde Dextran Obtained by Radiochemical Oxidation of Dextran

Tuberculous granulomas were found in all parenchymal organs of mice infected with mycobacteria of BCG vaccine. The number and size of hepatic granulomas decreased, while the count of degenerated and necrobiotic hepatocytes in infected animals increased 3 months after the start of therapy with a composition of isoniazid and dialdehyde dextran. The composition of isoniazid and dialdehyde dextran obtained by radiochemical oxidation of dextran had greater therapeutic efficacy and lower hepatotoxicity. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 73–75, 2008     

Structural Changes in the Liver Parenchyma and Granulomas of Mice with Chronic BCG Granulomatosis during Therapy with Composition of Isoniazid and Dialdehyde Dextran

Male BALB/c mice were intraperitoneally infected with BCG vaccine. The therapy with isoniazid or composition of isoniazid with dialdehyde dextran (intraperitoneally, twice a week for 5 months) was started 1 month after infection. The retention time of the isoniazid-dialdehyde dextran composition in hepatocytes was much longer compared to that of isoniazid. The mice receiving the composition of isoniazid and dialdehyde dextran were characterized by a more significant decrease in the number and size of BCG granulomas, lower severity of destructive changes in the liver parenchyma, and more pronounced reparative regeneration (compared to animals of the isoniazid group). Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 116–119, 2008     

Morphological Study of the Efficiency of Isoniazid and Dialdehyde Dextran Composition in the Treatment of Mice with BCG Granulomatosis

Male BALB/c mice were intraperitoneally injected with BCG vaccine. After 1 month therapy was started: isoniazid or composition of isoniazid with dialdehyde dextran (CID) obtained by chemical and radiochemical methods. The therapeutic efficiency evaluated by the number granulomas in the liver and lungs and granuloma size was higher in mice treated with CID obtained by the radiochemical method in comparison with mice treated with isoniazid and with CID obtained by the chemical method. Hepatotoxicity evaluated by volume density of degenerative hepatocytes and necrotic zones was higher in mice treated with CID obtained by the radiochemical method than in animals treated with isoniazid, because CID contained free isoniazid and isoniazid bound to dialdehyde dextran. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 105–108, 2008     

Survey of neonatal candidiasis in Greece

In order to estimate the extent of neonatal candidiasis in Greece and to identify trends in clinical management, the present study was conducted using a questionnaire directed to Greek neonatologists and pediatric infectious disease specialists. The respondents represented 15 hospitals in the country’s seven largest cities, which are currently the only Greek cities with neonatal intensive care units. Based on the responses, the incidence of neonatal candidiasis was determined to be 1.87 and 1.94 cases per unit-year for the years 2001 and 2002, respectively. Although a shift toward the isolation of non-Candida albicans isolates was noted, C. albicans was still the predominant pathogenic species. Deoxycholate amphotericin B remains the most frequently used antifungal agent in neonatal units nationwide.     

Ultrastructural characteristics of type A epithelioid cells during BCG-granulomatosis and treatment with lysosomotropic isoniazid

We studied BCG-granulomas, their cellular composition, and ultrastructure of type A epithelioid cells in the liver of male BALB/c mice with spontaneous granulomatous inflammation. The animals received free isoniazid or isoniazid conjugated with lysosomotropic intracellularly prolonged matrix (dialdehyde dextran, molecular weight 65–75 kDa). Lysosomotropic isoniazid was accumulated in the vacuolar apparatus of epithelioid cells and produced a stimulatory effect on plastic processes in these cells. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 4, pp. 474–477, April, 2006     

Effect of Dialdehyde Dextran on Structural Changes in the Liver and Lungs during Chronic BCG Granulomatosis

Male BALB/c mice were intraperitoneally infected with BCG vaccine. Cytomorphological changes in BCG granulomas of the liver and lungs were compared during spontaneous tuberculous inflammation and after intraperitoneal injection of dialdehyde dextran for 5 months. Administration of dialdehyde dextran to mice infected with mycobacteria of BCG vaccine was followed by a decrease in the number and size of BCG granulomas in organs, contributed to the increase in the count of fibroblasts in hepatic and pulmonary granulomas, decreased the severity of destructive changes in the liver parenchyma, promoted reparative processes in hepatocytes, and reduced the degree of fibrosis in the liver and lungs due to a decrease in fibroplastic activity of fibroblasts in BCG granulomas. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 113–115, 2008     

Activity of amphotericin B and itraconazole against intraphagocyticCandida albicans

The activity of amphotericin B and itraconazole against intracellularCandida albicans was determined in vitro using murine resident peritoneal macrophages. Amphotericin B at concentrations of 0.5 and 2 µg/ml produced significantly less rapid killing of intracellular than of extracellularCandida albicans as measured in macrophage-free medium. Amphotericin B at concentrations of 0.1 µg/ml or itraconazole concentrations of up to 3 µg/ml produced only fungistatic or limited fungicidal activity against both intracellular and extracellular organisms. Against intracellularCandida albicans amphotericin B acted by direct antifungal action rather than through stimulation of macrophage function, as demonstrated by the fact that (i) activity persisted when macrophages were successively exposed to amphotericin B, washed and disrupted by sonication, and (ii) no activity was seen when amphotericin B was tested against intracellular amphotericin B-resistantCandida tropicalis orSalmonella typhimurium. Pre-exposure of macrophages to itraconazole (0.4 µg/ml) inhibited subsequent killing activity of amphotericin B (2 µg/ml) against intracellular susceptibleCandida albicans. These experiments validate the conventional methods of susceptibility testing for determining the fungistatic activity of antifungal agents.     

<Emphasis Type="Italic">Candida albicans</Emphasis> enhances experimental hepatic melanoma metastasis

Candida albicans infections are very frequent in cancer patients, whose immune system is often compromised, but whether this fungal pathogen affects cancer progression is unknown. C. albicans infection involves endogenous production of inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-18 (IL-18). Increased levels of these cytokines have already been correlated with metastasis of most common cancer types. In this study, a well-established model of IL-18-dependent hepatic melanoma metastasis was used to study whether C. albicans can alter the ability of murine B16 melanoma (B16M) cells to colonize the liver. First, we determined the ability of intrasplenically (IS) injected B16M cells to metastasize into the liver of mice challenged with 5 × 10⁴ C. albicans cells by three different routes (intravenous, IV; intrasplenic, IS; or intraperitoneal, IP) 12 h prior to injection of B16M cells. We demonstrated that C. albicans significantly increased metastasis of B16M cells with all three fungal injection routes. Pro-metastatic effects occurred when hepatic colonization with B16M cells place after the peak of TNF-α and IL-18 levels had been reached in the hepatic blood of fungal challenged mice. In a second set of experiments, mice were fungal challenged 4 days after injection of B16M cells. In these mice, C. albicans also potentiated the growth of established micro-metastases. Significantly, the fungal challenge had pro-metastatic effects without the C. albicans being able to reach the liver, suggesting that soluble factors can promote metastasis in remote sites. Mouse treatment with antifungal ketoconazol abrogated hepatic TNF-α stimulation by C. albicans and prevented the enhancement of hepatic metastasis in fungal challenged-mice. Therefore, the pro-inflammatory microenvironment generated by the host’s systemic response to C. albicans stimulates circulating cancer cells to metastasize in the liver.     

Mononuclear phagocyte system in mice with intrauterine Candida albicans infection and postnatal experimental tuberculosis

Intrauterine Candida albicans infection in mouse fetuses affected the type of granulomatous inflammation induced by BCG vaccine during the postnatal period. It manifested in increased formation of granulomas and variations in their cellular composition. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 1, pp. 103–106, January, 2006     

Candida albicans biofilms formed into catheters and probes and their resistance to amphotericin B

In Algeria, many bacterial biofilms have been studied but those of fungal origin, particularly those due to the yeast Candida albicans remained unidentified. The present study was performed at the Chabane Hamdoune hospital in Maghnia (Algeria), where 51 strains of C. albicans representing 16.94% of all taken samples were isolated. They were collected from catheters and probes used in different hospital services with variable rates; the most concerned service was ICU (40.74%) followed by gynecology department (17.39%), while general surgery came third (15.79%). Testing the antifungal property of amphotericin B (AmB) we showed clearly that the sessile cells of C. albicans were much more resistant than their planktonic counterparts (suspended cells), especially when the resistance increased during the different phases of biofilm formation until it reached its threshold at the ripening stage (at 48 h). Furthermore, scanning electron microscopy of the isolated strains in the laboratory revealed the formation of biofilms on catheters by C. albicans. Surprisingly, observations revealed the presence of a new structure in these biofilms: a chlamydospore?     

In Vitro Effect of Oxidized Dextrans on Peritoneal Cells

We studied the dependence of in vitro dextran biocompatibility on the method of oxidation of 35-kDa dextran. The biocompatibility of dextran oxidized with potassium permanganate was higher compared to that obtained by radiochemical oxidation. It was related to the formation of peroxide compounds during radiochemical oxidation. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 120–122, 2008     

Morphological changes in the brain of mice with systemic candidiasis treated with composition of amphotericin B and oxidized dextran

We observed morphological manifestation of encephalitis 3, 7, 10 and 28 days after intravenous infection of adult male CBA mice with Candida albicans. Compounds were administered intraperitoneally every other day starting from the next day postinfection. Untreated animals (100%) died over the period between days 18 and 20 postinfection; 60% animals receiving oxidized dextran alone survived by day 28 of observation. All animals treated with amphotericin B and composition of amphotericin B and oxidized dextran survived. On day 3 postinfection, the count of macrophage infiltrates and granulomas in the cerebral interstitium of mice treated with amphotericin B was equal to that in untreated mice, but was sufficiently lower in animals treated with the composition or oxidized dextran alone. On day 10, this index was similar in all groups and was approximately 5 times lower than in untreated animals on day 3. On day 28, macrophage infiltrates and granulomas were absent in the brain of all treated mice. These data suggest that oxidized dextran produced a therapeutic effect, which manifested earlier than the effect of amphotericin B and potentiated its effect, probably due to its competition with Candida albicans for mannose receptors on the brain-blood barrier endothelium.     

Species distribution and antifungal susceptibility of Candida bloodstream isolates in a tertiary medical center in Israel

To evaluate the species distribution and antifungal susceptibility of Candida isolates in a tertiary institution in Israel, all consecutive isolates of Candida spp. recovered from blood during the last 2 years were studied. The isolates were identified by the germ tube test and the API ID 32C test (bioMérieux, Marcy l'Etoile, France). MICs of antifungal agents were determined by the E test. Candida albicans was the most commonly isolated species, accounting for 44% (63/142) of the isolates, followed by Candida tropicalis (25%; 35/142), Candida parapsilosis (20%; 29/142), Candida glabrata (10%; 14/142), and Candida krusei (0.7%; 1/142). All isolates were sensitive to amphotericin B and voriconazole. Resistance to fluconazole (using a high MIC of ≥256 μg/ml) was found in 1.6% of C. albicans isolates, in 3.4% of C. parapsilosis isolates, and in 21.4% of C. glabrata isolates. Resistance to itraconazole was detected in 3.2% of C. albicans isolates, in 2.9% of C. tropicalis isolates, in 3.4% of C. parapsilosis isolates, and in 93% of C. glabrata isolates. Disparities in species distribution and antifungal susceptibility of Candida isolates from the institute studied versus Candida isolates from other centers and countries are described. The findings emphasize the need for continuous surveillance and further clinical investigational studies.     

In vitro activity of antifungal combinations against planktonic and sessile cells of Candida albicans isolated from medical devices in an intensive care department

Background

Invasive fungal infections are an emerging health problem worldwide. They are responsible for a significant rate of morbidity and mortality. Infections caused by Candida albicans involve proliferation of biofilms on biotic or abiotic surface. These adherent communities exhibit characteristics distinct from planktonic cells such as the ability to tolerate high concentrations of antifungal.