Intestinal Decontamination Research Articles

Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression

BackgroundThere is a pressing need to identify novel pathophysiological pathways relevant to depression that can help to reveal targets for the development of new medications. Toll-like receptor 4 (TLR-4) has a regulatory role in the brain's response to stress. Psychological stress may compromise the intestinal barrier, and increased gastrointestinal permeability with translocation of lipopolysaccharide (LPS) from Gram-negative bacteria may play a role in the pathophysiology of major depression.MethodsAdult male Sprague-Dawley rats were subjected to chronic mild stress (CMS) or CMS+intestinal antibiotic decontamination (CMS+ATB) protocols. Levels of components of the TLR-4 signaling pathway, of LPS and of different inflammatory, oxidative/nitrosative and anti-inflammatory mediators were measured by RT-PCR, western blot and/or ELISA in brain prefrontal cortex. Behavioral despair was studied using Porsolt's test.ResultsCMS increased levels of TLR-4 and its co-receptor MD-2 in brain as well as LPS and LPS-binding protein in plasma. In addition, CMS also increased interleukin (IL)-1β, COX-2, PGE2 and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ2 in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ2, however this did not affect depressive-like behavior induced by CMS.ConclusionsOur results suggest that LPS from bacterial translocation is responsible, at least in part, for the TLR-4 activation found in brain after CMS, which leads to release of inflammatory mediators in the CNS. The use of Gram-negative antibiotics offers a potential therapeutic approach for the adjuvant treatment of depression.

Rifaximin improves thrombocytopenia in patients with alcoholic cirrhosis in association with reduction of endotoxaemia

Thrombocytopenia is a major haematological disorder of cirrhosis with unclear pathogenesis. Endotoxaemia resulting from intestinal bacterial overgrowth could reduce platelet counts directly or through cytokine release. To correlate endotoxaemia with platelet counts and study the effects of intestinal decontamination with rifaximin on thrombocytopenia in relation to changes in endotoxin and cytokine concentrations in patients with alcoholic cirrhosis. Platelet counts, plasma endotoxin levels and serum interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels were measured in 23 thrombocytopenic cirrhotic patients (platelet count<150 000/μl) before and after 4-week treatment with rifaximin 1200 mg/d (n = 13) or no treatment (n = 10) and at baseline in 10 cirrhotic patients without thrombocytopenia; spleen size was measured at baseline in all patients. Endotoxin and IL-6 levels were significantly higher in patients with thrombocytopenia than in those without thrombocytopenia (2.76 ± 0.69 vs. 0.64 ± 0.09 EU/ml; P < 0.001 and 24.26 ± 3.38 vs. 2.66 ± 0.74 pg/ml; P = 0.001 respectively). Platelet counts were inversely correlated with endotoxin levels (r = -0.589; P = 0.003), Child-Pugh score (r = -0.625; P = 0.001), IL-6 levels (r = -0.464; P = 0.02) and spleen size (r = -0.455; P = 0.02) in patients with thrombocytopenia. Following rifaximin, platelet counts increased significantly (83 100 ± 9700 vs. 99 600 ± 11 200/μl; P = 0.006) in line with significant reductions in endotoxin (1.28 ± 0.41 vs. 2.54 ± 0.86 EU/ml; P = 0.005), IL-1 (3.1 ± 0.5 vs. 4.4 ± 1.2 pg/ml; P = 0.04), IL-6 (12.8 ± 2.5 vs. 21.1 ± 4.2 pg/ml; P = 0.01) and TNF-α (3.6 ± 1.3 vs. 5.8 ± 1.7; P = 0.02) levels. Platelet count changes were correlated with the changes in endotoxin (r = 0.573; P = 0.04), TNF-α (r = 0.554; P = 0.05) and IL-6 (r = 0.495; P = 0.07) levels. Rifaximin improves cirrhosis-related thrombocytopenia and this could be related with the reduction of endotoxaemia.

Selective intestinal decontamination with fluoroquinolones for the prevention of early bacterial infections after liver transplantation

The role of selective intestinal decontamination with fluoroquinolones (FQ-SID) in the prevention of early bacterial infections (EBIs) in liver transplant recipients (LTRs) is unknown. We used the online database of the Spanish Network of Infection in Transplantation/Spanish Network for Research in Infectious Diseases, which prospectively analyzed 1010 LTRs from 12 Spanish hospitals from September 2003 to February 2005. We compared the incidence and etiology of EBIs (30 days after transplantation) in 415 LTRs from 4 centers that used FQ-SID (>7 days) and in 595 LTRs from 8 hospitals that did not use FQ-SID. A multivariate logistic regression analysis (including an adjustment for the transplant center factor) was performed to evaluate the potential protective factor of FQ-SID in the development of EBIs. We reported 266 EBI episodes in 252 LTRs (incidence = 24.9%). There were no differences in the incidence of EBIs between patients in the FQ-SID group and patients not in the FQ-SID group [109/415 (26.3%) versus 143/595 (24%), P = 0.9]. Although LTRs who received FQ-SID had a lower incidence of infections due to enteric bacteria (2.7% versus 6.5%, P = 0.007) and a higher incidence of infections due to nonfermenting gram-negative bacilli (6.6% versus 2.6%, P = 0.004), these findings could not be confirmed after an adjustment by the center factor in the multivariate models. We found no significant differences in the incidence of enterococcal infections (3.4% with FQ-SID versus 3.9% without FQ-SID, P = 0.5). Multivariate analysis did not confirm any protective effect of FQ-SID against the development of EBIs by enteric bacteria. In conclusion, FQ-SID does not reduce the incidence of EBIs in LTRs and could be withheld from this group of patients.

Passing the bug—Translocation, bacteremia, and sepsis in the intensive care unit patient: Is intestinal decontamination the answer?*

Alimentary Pharmabiotic Centre; Department of Medicine; University College Cork; Cork, Ireland The author has received funding from the Science Foundation. He has not disclosed any other potential conflicts of interest.

Ventilator-Associated Pneumonia: Preventing the Inevitable

Ventilator-associate pneumonia (VAP) is the most common nosocomial infection in patients in intensive care units (ICU). Because of its association with unwanted clinical outcomes, preventive measures have been studied intensively in the past 25 years. Unfortunately, a large amount of clinical trials yielded disappointingly few clear-cut answers. Furthermore, because of the difficulties in reliably diagnosing VAP, we should be very reluctant in embracing measures that have been associated with VAP reductions in small-sized studies, but with no benefits on patient outcome documented in sufficiently powered well-designed trials. Only topical antimicrobial prophylaxis (either alone in the oropharynx or in combination with intestinal decontamination) has been demonstrated to improve patient outcome resulting from prevention of VAP. However, this was demonstrated in not-so-average circumstances-in ICUs with extremely low levels of antibiotic resistance. Despite the obvious challenges with using antibiotics as preventive measures, careful evaluation of these strategies in settings with higher drug-resistance levels is now justified, and future studies should be designed to demonstrate outcome benefits rather than reductions in VAP rates.

Recurrence of spontaneous bacterial peritonitis in cirrhotic patients non-prophylactically treated with norfloxacin: serum albumin as an easy but reliable predictive factor

Several large studies revealed that selective intestinal decontamination (SID) prevented recurrence of spontaneous bacterial peritonitis (SBP) in cirrhotic patients. Nonetheless, there are no definitive patient selection parameters identifying who would benefit from SID. To investigate long-term outcomes in cirrhosis patients with recurrence of SBP and to identify predictive factors for SBP recurrence. We retrospectively studied 146 cirrhosis patients diagnosed with a first episode of SBP from 2005 to 2006. Of these, 89 patients survived; the survivors were divided into two groups based on recurrence and non-recurrence of SBP, and clinical parameters, survival time and cause of death were analysed. The in-hospital mortality was 39% (57/146). The SBP recurrence rate was 42.7% (38/89). The survival rate between patients with recurrent SBP and those without recurrence did not differ (P=0.092). Sepsis was the major cause of death in the recurrent SBP group, but not in the non-recurrent group. Serum albumin level before discharge and β-blocker use between the two groups differed significantly (P<0.0001). Using the cut-off point for serum albumin level before discharge of 2.85 g/dl as a predictor for recurrence of SBP, the sensitivity was 70.2% and the specificity was 76.3%. Furthermore, long-term survival of the group with high albumin before discharge was better than that of the corresponding group with low albumin (P=0.007). Spontaneous bacterial peritonitis was associated with high sepsis-related mortality in cirrhotic patients. Serum albumin before discharge was a useful single parameter to predict the recurrence of SBP and long-term survival.

The normal flora may contribute to the quantitative preponderance of myeloid cells under physiological conditions

Under physiological conditions, the innate immune cells derived from myeloid lineage absolutely outnumber the lymphoid cells. At present, two theories are attributed to the maintenance of haemopoiesis: the asymmetric cell division and the bone marrow hematopoietic microenvironment or "niche". However, the former only explains the self-renewal of haemopoietic stem cell (HSC) and the start of haemopoietic differentiation but fails to address the inducers of cell fate decisions; the latter has to admit that the hematopoietic cytokines, despite their significance in the maintenance of haemopoiesis, have no specific effect on lineage commitment. Given these flaws, the advantageous mechanism of myeloid haemopoiesis has not yet been uncovered in the current theories. The discoveries that bacterial components (lipopolysaccharide, LPS) and intestinal decontamination affect the mobilization of HSC trigger the interest in normal flora, which together with their components may have an effect on haemopoiesis. In the experiments in dogs and mice, researchers documented that the generation of myeloid cells has undergone changes in the bone marrow and periphery when antibiotics are used to regulate the normal intestinal flora and the concentration of its components. However, the same changes are not involved in lymphoid cells. Therefore, we hypothesize that in human body normal flora and its components are a driving force to maintain myeloid haemopoiesis under physiological conditions. To account for the selectiveness in haemopoiesis, these facts should be taken into consideration, such as HSC and mesenchymal stem cells (MSC) functionally expressed pattern recognition receptors (PRR), and both of them can self-migrate or be recruited by normal flora or its components into periphery. Dynamically monitoring the myeloid haemopoiesis may provide an important complementary program that precludes the abuse of antibiotics, which prevents diseases triggered by the imbalance of normal flora. Meanwhile, the regulation of normal flora and the use of purified microecological modulator may serve as valuable auxiliary treatments to mobilize HSC prior to the HSC transplantation as well as to promote hematopoietic recovery after transplantation or chemotherapy in the blood diseases.

Therapeutic strategies and emergence of multiresistant bacterial strains

Spontaneous bacterial peritonitis (SBP) is one of the most serious complications occurring in cirrhotic patients with ascites. Therefore, an effective therapy is always required starting immediately after diagnosis. There are three aims of therapy: (1) to eradicate the bacterial strain responsible of the infection; (2) to prevent renal failure; and (3) to prevent SBP recurrence. The first end point is achievable by means of a large-spectrum antibiotic therapy. Empirical antibiotic therapy can be started with a third-generation cephalosporin, amoxicillin-clavulanate or a quinolone. The effectiveness of antibiotics should be verified by determining the percent reduction of polymorphonuclear cells count in the ascitic fluid. If bacteria result to be resistant to the empirical therapy, a further antibiotic must be given according to the in vitro bacterial susceptibility. In most cases, a 5-day antibiotic therapy is enough to eradicate the bacterial strain. Severe renal failure occurs in about 30% of patients with SBP, independently of the response to antibiotics, and it is associated with elevated mortality. The early administration of large amount of human albumin showed to be able to reduce the episodes of renal failure and to improve survival. After the resolution of an episode of SBP, the recurrence is frequent. Therefore, an intestinal decontamination with oral norfloxacin has been shown to significantly reduce this risk and is widely practised. However, such a long-term prophylaxis, as well as the current increased use of invasive procedures, favours the increase of bacterial infections, including SBP, contracted during the hospitalization (nosocomial infections) and sustained by multi-resistant bacteria. This involves the necessity to use a different strategy of antibiotic prophylaxis as well as a more strict surveillance of patients at risk.

Endotoxaemia in the pathogenesis of cytopenias in liver cirrhosis. Could oral antibiotics raise blood counts?

Cytopenias are frequently observed in patients with cirrhosis and are associated with increased morbidity. In particular, thrombocytopenia can impact routine care of patients with cirrhosis by potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy and medically indicated or elective surgery. The pathogenesis of cytopenias in cirrhosis remains largely unknown. Historically, the concept of hypersplenism has long been associated with the cirrhosis-related hematological disorders but was never proven. On the other hand, intestinal bacterial overgrowth and altered gut permeability in cirrhotic patients lead to increased translocation of bacteria and endotoxin into the portal circulation. The impaired phagocytic function of the reticuloendothelial system together with the portosystemic shunting allow endotoxin to reach the systemic circulation and high concentrations of circulating endotoxin are found in cirrhotic patients even with no clinical evidence of infection and correlate with the severity of liver disease. Endotoxin activates monocytes and promotes the release of proinflammatory cytokines. Indeed, serum levels of interleukin-1, interleukin-6, tumor necrosis factor-α, and interferon-γ are elevated in patients with cirrhosis in proportion to the severity of liver disease. Endotoxaemia stimulates the vascular production of nitric oxide (NO) directly or indirectly via the cytokine cascade, and correlates with serum NO metabolite levels in cirrhosis. Several lines of evidence strongly suggest that endotoxaemia may reduce peripheral blood counts either directly or through the release of cytokines and NO. Previous studies in experimental models of cirrhosis and cirrhotic patients have demonstrated that long-term administration of oral antibiotics such as trimethoprim-sulfamethoxazole, norfloxacin, and rifaximin can reduce bacterial translocation and circulating levels of endotoxin, TNF-α, IL-6, and NO. We hypothesize that endotoxaemia plays a pivotal role in the pathogenesis of cytopenias in cirrhosis and that intestinal decontamination could raise peripheral blood counts by the suppression of endotoxaemia and the inhibition of cytokine and NO production.

Norfloxacin Modulates the Inflammatory Response and Directly Affects Neutrophils in Patients With Decompensated Cirrhosis

Patients with cirrhosis undergoing selective intestinal decontamination with norfloxacin show a reduction in serum cytokine levels, probably because of a combined effect of norfloxacin on bowel flora and neutrophils. Thirty-one patients with cirrhosis receiving norfloxacin (400 mg/day) were included. Blood samples were collected at 0.5-4 hours (peak samples group, n = 47) and at 22-24 hours (trough samples group, n = 84) after dose. Fifty-nine ascitic fluid samples were obtained. Single doses of norfloxacin and trimethoprim/sulfamethoxazole were administered to 13 and 5 patients, respectively, (temporal profile group) and samples were collected at 0, 0.5, 1, 1.5, 2, 4, and 24 hours. Norfloxacin, trimethoprim/sulfamethoxazole, cytokines, nitric oxide, expression levels of nuclear factor (NF)-kappaB and inhibitor of NF-kappaB (IkB-alpha), neutrophil oxidative burst, and rate of apoptotic events were determined. All samples were bacterial DNA negative and had no significant levels of lipopolysaccharide. Serum and ascitic levels of tumor necrosis factor-alpha, interferon-gamma, interleukin-12, and nitric oxide were significantly lower in peak than in trough samples. A correlation was present between serum norfloxacins concentrations and tumor necrosis factor-alpha (r = -0.68; P < .001), interferon-gamma (r = -0.66; P < .001), interleukin-12 (r = -0.66; P < .001), and nitric oxide (r = -0.68; P < .001). Serum norfloxacin's highest concentrations (1 +/- 0.5 microg/mL) were achieved at 1-2 hours and concurred in time with the lower levels of cytokines and nitric oxide. Intracellular norfloxacin's highest levels (2 +/- 1 microg/mL/10(7) cells) were observed at 2 hours and concurred with a lower NF-kappaB expression, a reduced anion superoxide generation, and apoptotic rate in response to phorbol myristate acetate. Trimethoprim/sulfamethoxazole did not significantly modulate cytokine expression. Norfloxacin but not trimethoprim/sulfamethoxazole modulates inflammatory response and directly affects neutrophils in patients with cirrhosis.

Does debugging the portal system decrease pressure?

Sirs, Bacteria and their products (DNA, endotoxin and cytokines) may contribute not only to deteriorate hyperdynamic circulation, but also to increase hepatic vascular resistance in cirrhotic patients, promoting by this way a further increase in portal pressure. Bacterial infections have been proposed as triggers for variceal bleeding and have been shown to be associated with a poor prognosis.1 As a consequence, whether antibiotics may contribute to ameliorating portal pressure in cirrhosis has been a matter of debate. Indeed, three studies had previously evaluated this issue (Table 1). Only two of them showed the effects of placebo on hepatic venous pressure gradient (HVPG) and the effect was completely equivalent to that of norfloxacin.2,3 In a third study,4 a nonsignificant trend to reduce HVPG was observed. However, this study did not evaluate the effect of placebo on HVPG and less than half of the patients had clinically significant portal hypertension (HVPG > 10 mmHg). A recent study published in Alimentary Pharmacology and Therapeutics5 provides novel data testing the possible efficacy of antibiotics in lowering portal pressure. The investigators treated for 1 month patients with decompensated alcoholic cirrhosis with rifaximin, a nonsystemically absorbed antibiotic, and observed a significant decrease in plasma endotoxin levels, which directly correlated with a significant drop in HVPG. The authors concluded that intestinal decontamination with rifaximine might represent a therapeutic approach in the prevention of complications of portal hypertension. The major drawback of this study was the absence of a control group. Indeed, similar effect on HVPG was observed in the two studies that had data on the effect of norfloxacin and placebo on HVPG, thus highlighting the importance of excluding other possible factors biasing the results like, for example, alcohol abstinence. The potential interest of these findings was further faded by the absence of follow-up data on the outcome of their patients during the study period. Therefore, these results should be considered preliminary and need to be confirmed. We must wait for additional studies with appropriate design and sample size to define clearly the possible role of antibiotics to improve the hemodynamic disturbances of cirrhotic patients. Declaration of personal and funding interests: The writing of this paper was funded in part by the Swiss National Science Foundation, the EASL Sheila Sherlock Fellowship. Ciberehd is funded by Instituto de Salud Carlos III.

Lack of effect of norfloxacin on hyperdynamic circulation in bile duct‐ligated rats despite reduction of endothelial nitric oxide synthase function: result of unchanged vascular Rho‐kinase?

In cirrhosis, portal hypertension is maintained by splanchnic vasodilation owing to overproduction of the vasodilator nitric oxide (NO) and defective contractile signalling by Rho-kinase. NO overproduction is partially caused by bacterial translocation from the gut to mesenteric lymph nodes. However, the effects of intestinal bacterial decontamination on hyperdynamic circulation or vascular contractility are unknown. We investigated the haemodynamic and vascular effects of norfloxacin in rats with secondary biliary cirrhosis. Cirrhosis was induced by bile duct ligation (BDL). One group was treated with norfloxacin (20 mg/kg/day, 5 days, orally). Bacterial growth in the lymph nodes was determined on blood agar plates. Invasive haemodynamic measurements were combined with coloured microspheres. Aortic contractility was assessed myographically. Protein expression/phosphorylation was examined by Western blot analysis. Norfloxacin treatment of BDL rats abolished bacterial translocation to mesenteric lymph nodes. BDL rats had hyperdynamic circulation, including portal hypertension and splanchnic vasodilation. None of these parameters was changed by norfloxacin, although norfloxacin reduced endothelial NO synthase expression and phosphorylation. The latter was associated with a diminished activity of protein kinase G (PKG), which mediates NO-induced vasodilation. However, norfloxacin had no effect on aortic contractility to methoxamine or Ca2+, or the aortic expression of RhoA, Rho-kinase and beta-arrestin 2, or the phosphorylation of the Rho-kinase substrate moesin. Short-term treatment of BDL rats with norfloxacin does not change hyperdynamic circulation or vascular contractility, despite reduction of PKG activity.

Antibiotic prophylaxis for spontaneous bacterial peritonitis in cirrhotic patients with ascites, without gastro-intestinal bleeding

Spontaneous bacterial peritonitis is frequent among cirrhotic patients, associated with significant morbidity and mortality. Selective intestinal decontamination employing antibiotics is a proposed prophylactic measure. While data regarding this modality among cirrhotic patients with gastrointestinal bleeding exist, there is insufficient data synthesis regarding cirrhotic patients with ascites and no gastrointestinal bleeding. To assess whether antibiotic prophylaxis decreases spontaneous bacterial peritonitis and mortality among cirrhotic patients with ascites and no gastrointestinal bleeding. We identified relevant randomised trials by searching trial registries of The Cochrane Hepato-Biliary Group and The Cochrane Collaboration, medical literature search engines, and reviewing all literature we found on the topic until February 2009. We searched for randomised clinical trials assessing prophylactic treatment among adult cirrhotic patients with ascites and no gastrointestinal bleeding, comparing antibiotic therapy with no intervention, placebo, or with another antibiotic regimen. Three independent authors searched for and collected the trials and extracted relevant data. Four other independent authors validated the findings and assessed them. The studies were assessed for design, patient and intervention characteristics, and quality. A meta-analysis was performed to estimate measures of association between antibiotic prophylaxis and spontaneous bacterial peritonitis or mortality. Nine trials were included in the review. Seven trials, comparing antibiotics to placebo or no treatment, were meta-analysed. Systematic bias in design or publication is suggested by trial results. The randomisation results suggest that the probability that true randomisation took place in all trials is very small and the report of most trials regarding design was poor. The proportion of participants with spontaneous bacterial peritonitis varied between the trials from 15% to 50%. The calculated relative risks (95% confidence interval) of spontaneous bacterial peritonitis and mortality among patients treated with antibiotics compared with no treatment/placebo were 0.20 (0.11 to 0.37) and 0.61 (0.43 to 0.87). There were very few reports of adverse events. The pooled estimates suggest that antibiotic prophylaxis might be prudent among cirrhotic patients with ascites and no gastrointestinal bleeding. However, poor trial methodology and report coupled with findings suggesting systematic bias in publication and design reflect the fragility of these findings. Potential hazard to society and the patients themselves from resistant pathogens should be considered when promoting long-lasting antibiotic prophylaxis. It seems that recommending antibiotic prophylaxis is still far from being a substantiated prevention strategy. Trials of better design, well reported, and of longer follow-up are greatly needed.

Intestinal decontamination improves liver haemodynamics in patients with alcohol‐related decompensated cirrhosis

Endotoxaemia is commonly seen in cirrhotic patients with ascites and this may be associated with increased portal pressure. To investigate the effect of intestinal decontamination on liver haemodynamics in alcohol-related cirrhotic patients with ascites. We included 30 patients. At day 0, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed. Patients received rifaximin (1200 mg/day) for 28 days. At day 29, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed again. Median (range) plasma endotoxin levels decreased significantly after rifaximin administration both in systemic [1.45(0-3.1) vs. 0.7(0-2.7), P < 0.0001] and splanchnic circulation [1.8(0-3.4) vs. 0.8(0-2.1), P < 0.0001]. Meanwhile, the difference seen in endotoxin levels between the splanchnic and systemic circulation at day 0 (P = 0.001) was not noted at day 29 (P = 0.137). HVPG measurement was possible in 28 patients. Median (range) HVPG values were 18 mmHg (12.7-26.3) on day 0 vs. 14.7 mmHg (7-20) on day 29 (P < 0.0001). HVPG decreased after rifaximin in 23, remained stable in two and increased in three patients. Hepatic venous pressure gradient values decreased significantly after intestinal decontamination with rifaximin in patients with alcohol-related decompensated cirrhosis and this might have been achieved through significant reduction of plasma endotoxin levels.

Norfloxacin treatment for clinically significant portal hypertension: results of a randomised double‐blind placebo‐controlled crossover trial

While selective intestinal decontamination (SID) can alter the hyperdynamic circulatory state of cirrhosis, the impact of SID on portal pressure remains unclear especially in the setting of clinically significant portal hypertension. To examine the impact of SID with norfloxacin on portal pressure in subjects with clinically significant portal hypertension and explore the potential mechanisms by which norfloxacin exerts its haemodynamic effects. Randomised, double blind, placebo-controlled, crossover trial of norfloxacin 400 mg twice daily for 4 weeks. The portal pressure was assessed by hepatic venous pressure gradient (HVPG). Endotoxaemia was assessed by the Limulus amebocyte lysate (LAL) assay. l-arginine (l-Arg) transporter function was assessed in peripheral blood mononuclear cells (PBMCs). Plasma levels of urotensin II (UII) and tumour necrosis factor were measured before and after therapy. Sixteen subjects with clinically significant portal hypertension (16.5+/-1.1 mmHg) completed the study. Norfloxacin therapy was not superior to placebo in reducing HVPG (13.8+/-1.0 mmHg vs 13.6+/-1.2 mmHg, P=0.3). Furthermore, no alteration in l-Arg transport was detected after 4 weeks of norfloxacin therapy. Plasma UII levels correlated positively with HVPG (P=0.01) and the Child-Pugh score (P<0.05). However, UII levels following therapy did not parallel HVPG changes. Norfloxacin is not superior to placebo in reducing HVPG in subjects with clinically significant portal hypertension. Furthermore, norfloxacin does not appear to modulate the l-Arg transporter mechanism in this patient population. Although plasma UII correlates positively with HVPG, UII does not appear to have a direct role in modulating HVPG.

Diagnostic work‐up and management of patients with isolated methylmalonic acidurias in European metabolic centres

The long-term outcome of patients with methylmalonic aciduria (MMA) is still uncertain due to a high frequency of complications such as chronic renal failure and metabolic stroke. The understanding of this disease is hampered by a huge variation in the management of these patients. The major aim of this study was to evaluate the current practice in different European metabolic centres. A standardized questionnaire was sent to 20 metabolic centres asking for standard procedures for confirmation of diagnosis, testing cobalamin responsiveness, dietary treatment, pharmacotherapy, and biochemical and clinical monitoring. Sixteen of 20 metabolic centres (80%) returned questionnaires on 183 patients: 89 of the patients were classified as mut(0), 36 as mut(-), 13 as cblA, 7 as cblB, and 38 as cblA/B. (1) Confirmation of diagnosis: All centres investigate enzyme activity by propionate fixation in fibroblasts; six centres also perform mutation analysis. (2) Cobalamin response: Ten centres follow standardized protocols showing large variations. A reliable exclusion of nonspecific effects has not yet been achieved by these protocols. (3) Long-term treatment: In cobalamin-responsive patients, most centres use hydroxocobalamin (1-14 mg/week i.m. or 5-20 mg/week orally), while two centres use cyanocobalamin. All cobalamin-nonresponsive patients and most cobalamin-responsive patients are supplemented with L: -carnitine (50-100 mg/kg per day). Fourteen centres use intestinal decontamination by antibiotic therapy. Most centres follow D-A-CH (n = 6) or Dewey (n = 4) recommendations for protein requirements. Fourteen centres regularly use precursor-free amino acid supplements. Standardized monitoring protocols are available in seven centres, again showing high variability.

Regarding the risk for development of surgical site infections and bacterial prophylaxis in liver transplantation

Regarding the risk for development of surgical site infections and bacterial prophylaxis in liver transplantation

Polyamine contents in current foods: a basis for polyamine reduced diet and a study of its long term observance and tolerance in prostate carcinoma patients

Polyamine contents were assessed by mass spectrometry in 233 current foods and beverages. In order to reduce gut polyamine uptake, a polyamine reduced diet (PRD) and partial intermittent intestinal tract decontamination (PIITD) with neomycin or nifuroxazide was proposed as nutritional therapy to 33 prostate carcinoma patients, 30 of whom with hormone refractory prostate cancer (HRPC). Mean PRD observance was 22 +/- 19 (median: 16; range: 3-72) months. 10, 8 and 3 patients were respectively on PRD for more than 30, 36 and 64 months. No diet toxicity was observed. 8 patients had moderate intestinal intolerance due to PIITD which was interrupted. No significant differences in body weight, blood counts or serum protein levels were observed during the follow-up of patients under PRD. Performance status and pain scores were relatively stable during the trial with improved pain scores at 6 months. A PRD associated with intermittent PIITD is a safe and well observed nutritional regimen and long term observance is possible.

Bacterial infections in cirrhosis

A bakteriális infekciók a májcirrhosis jól ismert szövődményei, jelentősen emelik a mortalitást. A májelégtelenség súlyossága és a gastrointestinalis vérzés fontos hajlamosító tényezők. A leggyakoribb fertőzések a spontán bakteriális peritonitis, a húgyúti és légúti fertőzések, valamint a sepsis. A kórokozók között azonos arányban fordulnak elő Gram-negatív és -pozitív baktériumok. Gastrointestinalis vérzés esetén (varix vagy nem varix eredetű) az ascites meglététől vagy hiányától függetlenül rövidtávú profilaktikus antibiotikus kezelés (per os norfloxacin vagy ciprofloxacin) javasolt (primer prevenció) . A kórházi kezelés ideje alatt gastrointestinalis vérzés hiányában is megfontolandó a norfloxacin adása alacsony ascites proteintartalom esetén. A spontán bakteriális peritonitis empirikus kezelésében iv. III. generációs cephalosporin adása javasolt, mely a tenyésztési lelet alapján célzott antibiotikus kezelésre váltható. A kezelés időtartama 5–8 nap. Jó alternatíva lehet az amoxicillin/klavulánsav kombináció, valamint korábban spontán bakteriális peritonitis profilaxisban nem részesülő betegek esetén valamely kinolonszármazék is. Az iv. megkezdett antibiotikus kezelés megfelelő klinikai javulás mellett 2 nap múlva per os kezelésre váltható. Veseelégtelenség társulása esetén kiegészítő albuminkezelés szükséges. Hosszú távú antibiotikum-profilaxis a spontán bakteriális peritonitis epizód lezajlását követően a gyakori kiújulás veszélye miatt minden betegnél indokolt (szekunder prevenció) . A „szelektív intestinalis dekontaminációra” leginkább a per os adott, elsősorban rosszul felszívódó fluorokinolonszármazék, a norfloxacin javasolt. A per os adott ciprofloxacin vagy méginkább a levofloxacin, ez utóbbi Gram-pozitívak ellen is hatékony, megfelelő alternatíva lehet. Trimetoprim/sulfamethoxazole adása csak abban az esetben jön szóba, ha a beteg nem kaphat kinolonszármazékot. A kezelést az ascites eltűnéséig; az ascites perzisztálása esetén a beteg élete végéig vagy a májtranszplantációig kell folytatni. A rezisztens törzsek kialakulásának veszélye miatt hosszútávú profilaxis spontán bakteriális peritonitisen még át nem esett asciteses cirrhosisos betegekben nem javasolt, akkor sem, ha az ascites terápia refrakter, vagy pedig fehérjetartalma alacsony.

Epidemiology and risk factors for colonization and infection by Acinetobacter baumannii in an ICU in Tunisia, where this pathogen is endemic

Because Acinetobacter baumannii has become an alarming endemic pathogen in our country we decided to conduct this prospective study, from January 2004 to December 2005, in order to determine risk factors and outcomes involved in clinical colonization or infection by A. baumannii in a 16-bed Tunisian intensive care unit (ICU). One hundred and two A. baumannii isolates were obtained from 63 patients, with an infection rate of 45%. The rate of multidrug-resistant (MDR) A. baumannii was 39% during the 2-year study, with an epidemic outbreak in October 2004. This outbreak was followed by closure of all the involved ICU rooms and the selective intestinal decontamination of patients, with polymyxin. During the 12-month post-intervention program (January-December 2005), the infection rate declined. The analysis of risk factors for the spread of A. baumannii showed that only the Simplified Acute Physiological Score (SAPS II) was involved. On the other hand, no risk factor was identified for multidrug resistance in patients either colonized or infected by A. baumannii. There was a statistically significant difference only in crude mortality (67.5% in MDR A. baumannii vs 46.7% in susceptible A. baumannii; P = 0.04).