Colistins offers proconged survival in experimetnal infection by multidrug - resistant acinetobacter baumanni the significance of co-administration of rifampin

Objective: To assess the efficacy of co-administration of colistin and rifaldin in experimental infection and sepsis by multidrug-resistant strain A. baumannii Design: 84 Wistar rats were studied four of them were used for the verification of neutropenia according to the protocol of cyclophosphamide. The rest of them (80 Wistar rats ) were divided in four groups of treatment (A to D) of 20 animals each. Setting: Acute infection as bacteremia induced after the intramuscular injection of the prepared inoculum of the isolate in the left thigh of the animals. Therapy was administrated five hours after bacterial challenge. Groups : A as controls; B - D therapy initiation as follows : B: rifampin as monotherapy C: colistin as monotherapy D: therapy with both agents rifampin and colistin Measurements: Survival was recorded in ten animals of each group.The remaining ten rats per group were sacrificed four hours after therapy; blood and tissue samples were sampled. Median survival of animals of groups A, B, C and D was 2.00, 2.50, 4.00 and 4.00 respectively. Statistically significant increase of median survival were found between A and C groups (p: 0.0048) and between groups A and D (p: 0.0012). Statistically significant decrease of bacteria were found in blood (p: 0.0001), liver (p : 0.001), lung (p: 0.042) and spleen (p: 0.044) of group B compared to A; in lung of group C compared to A (p : 0.011); and in blood (p: 0.0001) and liver (p:0.010) those of group D compared to A. Mean SE +/- concentrations of rifampin of group B were 8,92 +/- 1,74; those of group D were 5,14 +/- 0,67μgr/ml (pNS between groups). Mean SE +/- concentrations of colistin of group C were 1,27 +/- 0,57; those of group D were 1,83 +/- 1,13 μgr/ml (p NS between groups ). Conclusions: It is concluded that colistin was effective in prolonging survival in an experimental thigh infection by multidrug-resistant A.baumannii in neutropenic rats. Its activity was achieved by direct bacterial killing and it was enchanced after co-administration with rifampin. These results mandate the application of colistin in the event of infections by multidrug- resistant pathogens and the need of co-administration with rifampin.Σκοπός: Να εκτιμηθεί η αποτελεσματικότητα της συγχορήγησης της κολιμυκίνης με τη ριφαμπικίνη στην πειραματική βακτηριαιμία και σήψη από πολυανθεκτικό στέλεχος A.baumannii Σχεδιασμός: Eφαρμογή σε 84 επίμυες Wistar. Απ’ αυτούς οι 4 χρησιμοποιήθηκαν για την προκαταρκτική πρόκληση ουδετεροπενίας και οι υπόλοιποι 80 χωρίστηκαν σε 4 ομάδες των 20 που έλαβαν την ανάλογη θεραπεία.( ομάδες από Α έως Δ). Ομάδες : H ομάδα Α ομάδα ελέγχου Η ομάδα Β στην οποία χορηγήθηκε ριφαμπικίνη ως μονοθεραπεία Η ομάδα Γ στην οποία χορηγήθηκε κολιμυκίνη ως μονοθεραπεία Η ομάδα Δ στην οποία έγινε συγχορήγηση των δύο αντιμικροβιακών παραγόντων Διενεργηθείσες μετρήσεις : Εκτίμηση της επιβίωσης, ενδοτοξίνες του ορού και συγκεντρώσεων των αντιβιοτικών στο αίμα. Ιστοτεμάχια πνεύμονα, ήπατος και σπληνός καλλιεργήθηκαν ποσοτικά. Αποτελέσματα : H μέση επιβίωση για τα ζωϊκά πρότυπα της ομάδας Α ήταν 2,00 ημέρες, για εκείνα της ομάδας Β ήταν 2,50 ημέρες, για εκείνα της ομάδας Γ 4,00 ημέρες και για τα ζώα της ομάδας Δ ήταν 4,00 ημέρες. Μετά την εφαρμογή της κατά Bonferroni διόρθωσης οι σημαντικότερες στατιστικά διαφορές παρουσιάζονται ανάμεσα στις ομάδες Α και Γ καθώς και ανάμεσα στις ομάδες Α και Δ (p : 0.0048) και (p : 0.0012) αντίστοιχα. Ο αριθμός των βακτηρίων στο αίμα, στο ήπαρ, στο σπλήνα και στον πνεύμονα όσον αφορά στην ομάδα Β σε σχέση με την ομάδα Α ήταν χαμηλότερος στο αίμα (p:0.0001), στο σπλήνα (p: 0.044), στο ήπαρ (p : 0.001) και στον πνεύμονα (p : 0.042). Τα βακτήρια της ομάδας Γ ήταν λιγότερα σε σχέση με την ομάδα Α στον πνεύμονα (p : 0.011) κι εκείνα της ομάδας Δ ήταν λιγότερα απ’ αυτά της ομάδας Α στο αίμα (p : 0.0001) και στο ήπαρ (p : 0.010). Η μέση συγκέντρωση της ριφαμπικίνης για την ομάδα Β ήταν 8,92 ± 1,74 και εκείνη της ομάδας Δ ήταν 5,14 ± 0,67 μgr/ml (pNS μεταξύ των ομάδων). Η μέση συγκέντρωση της κολιμυκίνης της ομάδας Γ ήταν 1,27 0, ± 57 κι εκείνη της ομάδας Δ ήταν 1,83 1, ± 13 μgr/ml (pNS μεταξύ των ομάδων ). Συμπεράσματα : Η συγχορήγηση κολιμυκίνης και ριφαμπικίνης αποτελεί έναν ασφαλή και ενδεδειγμένο τρόπο για τη διευθέτηση της βακτηριαιμίας και της συνακόλουθης σήψης της προκαλούμενης από πολυανθεκτικό στέλεχος A.baumannii. Η αποτελεσματικότητά τους αποδείχτηκε όταν χορηγήθηκαν μετά από πεντάωρη δράση του πολυανθεκτικού μικροβιακού παράγοντα. Τα παραπάνω αποτελέσματα εντείνουν την ανάγκη για τη διενέργεια περαιτέρω κλινικής έρευνας για τη θεραπεία της σήψης της οφειλόμενης σε πολυανθεκτικά στελέχη A.baumannii

Serum Leptin, Adiponectin and Tumor Necrosis Factor-alpha in Hyperlipidemic Rats with/without Concomitant Diabetes Mellitus

We compared the lipid profiles and serum levels of leptin, adiponectin and tumor necrosis factor-alpha (TNF-alpha) in rats with/without hyperlipidemia and with/without concomitant diabetes mellitus. Forty 10-wk-old male Wistar rats were divided into four groups. Groups A and C received standard food for 12 wks. Groups B and D received a high-fat diet enriched with 2% additional cholesterol. Moreover, insulin-deficient (type I) diabetes mellitus was induced in rats in groups C and D with intraperitoneal injections of streptozotocin. Fasting serum leptin levels were decreased in diabetic groups (groups C and D) compared with controls. Fasting serum adiponectin levels were decreased in groups C and D compared with group A. Serum TNF-alpha levels were augmented in groups B and D, those fed with an atherogenic diet. By contrast, TNF-alpha levels were decreased in group C. Our data suggest that serum leptin, adiponectin and TNF-alpha levels may serve as markers of obesity and type I diabetes mellitus. (c) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2010.0016

Effects of direct infusion of bone marrow-derived progenitor cells and indirect mobilization of hematopoietic progenitor cells on atherosclerotic plaque and inflammatory process in atherosclerosis

Background: We sought to investigate the effects of lin-/sca+ cells, endothelial progenitor cells (EPCs) and granulocyte colony-stimulating factor (G-CSF) administration on atherosclerotic plaque progression. Methods: Apolipoprotein E-deficient (apoE(-/-)) mice were splenectomized and treatedwith high-cholesterol diet for 6 weeks in order to induce atherosclerotic plaque development. Bone marrow-derived Lin-/sca-1+ cells were isolated and further cultured to early growth endothelial progenitor cells (EPCs). Mice were divided in four groups (n = 10/group) and received two intravenous injections of 5 x 105 cells (lin-/sca-1+ or EPCs), or granulocyte colony-stimulating factor (G-CSF 100 mu g/kg/day) for 7 days or normal saline. The same interventions were administered to animals, which had undergone unilateral hind-limb ischemia. Effects on inflammatory parameters, lesion severity, and atherosclerotic plaque area size were assessed. Results: The administration of both G-CSF and progenitor cells significantly decreased the levels of IL-6, 6 weeks after the initiation of treatment. Atherosclerotic lesion area was reduced by G-CSF (atherosclerotic plaque area percentage 22.94% +/- 3.68, p = 0.001), by lin-/sca-1+ (23.27% +/- 5.98, p = 0.002) and cultured EPCs (23.16 +/- 4.86%, p = 0.002) compared to control (32.75% +/- 7.05). In the atherosclerotic mice that underwent limb ischemia, the atherosclerotic plaque area, was not significantly different between the treatment groups cultured EPCs-treated mice and the control group (p = NS, for all). Conclusions: Direct infusion of progenitor cells and indirect mobilization of hematopoietic progenitor cells decreased plaque progression and levels of inflammatory molecules in a murine model of atherosclerosis. Treatment with G-CSF, lin-/sca-1+, or EPCsmay exert beneficial effects on vascular inflammation and atherosclerotic plaque progression. However, the effects are diminished in an ischemic setting. (C) 2013 Elsevier Ireland Ltd. All rights reserved

Comparison of Fibrate, Ezetimibe, Low- and High-Dose Statin Therapy for the Dyslipidemia of the Metabolic Syndrome in a Mouse Model

Background and Aim: The treatment-of-choice for the optimal management of the dyslipidemia of the metabolic syndrome (MetS) is not clearly defined. We compared the efficacy of 4 drug regimes for the management of this dyslipidemia in a mouse model. Materials and Methods: A total of 60 C57B16 mice comprised the study group. The first 10 received standard mouse food for the whole experiment (control group). The remaining 50 mice received atherogenic diet for 14 weeks until the development of the MetS. The mice were then divided into 5 groups: the 1st group continued receiving atherogenic diet, while the other 4 groups received atherogenic diet plus ezetimibe (10 mg/kg per day), fenofibrate (100 mg/kg per day), low-dose atorvastatin (10 mg/kg per day), or high-dose (40 mg/kg per day) atorvastatin, respectively, for another 8 weeks. Results: High-dose atorvastatin treatment achieved the best lipid profile compared with low-dose atorvastatin, ezetimibe, and fibrate therapy. The lipid profile of mice receiving atherogenic diet plus high-dose atorvastatin treatment was similar with mice on regular chow. Conclusions: High-dose atorvastatin treatment resulted in optimization of the lipid profile in the presence of a high-fat atherogenic diet in a mouse model. Our results suggest that high-dose atorvastatin treatment may be the optimal treatment option for the dyslipidemia associated with MetS. Nevertheless, verification of these results in humans is required before any definite conclusions can be drawn