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      Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study

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      BMJ : British Medical Journal
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          Abstract

          Objective To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome.

          Design Multicentre retrospective case-control study.

          Setting 23 hospitals in northern Germany.

          Participants 298 adults with enterohaemorrhagic E coli induced haemolytic uraemic syndrome.

          Main outcome measures Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death.

          Results 160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% v 15%, P=0.03), fewer deaths (0% v 5%, p=0.029), required no abdominal surgery, and excreted E coli for a shorter duration.

          Conclusions Enterohaemorrhagic E coli induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial.

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          Most cited references39

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          Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome.

          Most cases of diarrhoea-associated haemolytic uraemic syndrome (HUS) are caused by Shiga-toxin-producing bacteria; the pathophysiology differs from that of thrombotic thrombocytopenic purpura. Among Shiga-toxin-producing Escherichia coli (STEC), O157:H7 has the strongest association worldwide with HUS. Many different vehicles, in addition to the commonly suspected ground (minced) beef, can transmit this pathogen to people. Antibiotics, antimotility agents, narcotics, and non-steroidal anti-inflammatory drugs should not be given to acutely infected patients, and we advise hospital admission and administration of intravenous fluids. Management of HUS remains supportive; there are no specific therapies to ameliorate the course. The vascular injury leading to HUS is likely to be well under way by the time infected patients seek medical attention for diarrhoea. The best way to prevent HUS is to prevent primary infection with Shiga-toxin-producing bacteria.
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            The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections.

            Children with gastrointestinal infections caused by Escherichia coli O157:H7 are at risk for the hemolytic-uremic syndrome. Whether antibiotics alter this risk is unknown. We conducted a prospective cohort study of 71 children younger than 10 years of age who had diarrhea caused by E. coli O157:H7 to assess whether antibiotic treatment in these children affects the risk of the hemolytic-uremic syndrome and to assess the influence of confounding factors on this outcome. Estimates of relative risks were adjusted for possible confounding effects with the use of logistic-regression analysis. Among the 71 children, 9 (13 percent) received antibiotics and the hemolytic-uremic syndrome developed in 10 (14 percent). Five of these 10 children had received antibiotics. Factors significantly associated with the hemolytic-uremic syndrome were a higher initial white-cell count (relative risk, 1.3; 95 percent confidence interval, 1.1 to 1.5), evaluation with stool culture soon after the onset of illness (relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.8), and treatment with antibiotics (relative risk, 14.3; 95 percent confidence interval, 2.9 to 70.7). The clinical and laboratory characteristics of the 9 children who received antibiotics and the 62 who did not receive antibiotics were similar. In a multivariate analysis that was adjusted for the initial white-cell count and the day of illness on which stool was obtained for culture, antibiotic administration remained a risk factor for the development of the hemolytic uremic syndrome (relative risk, 17.3; 95 percent confidence interval, 2.2 to 137). Antibiotic treatment of children with E. coli O157:H7 infection increases the risk of the hemolytic-uremic syndrome.
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              Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice.

              Shiga toxin-producing Escherichia coli (STEC) cause significant disease; treatment is supportive and antibiotic use is controversial. Ciprofloxacin but not fosfomycin causes Shiga toxin-encoding bacteriophage induction and enhanced Shiga toxin (Stx) production from E. coli O157:H7 in vitro. The potential clinical relevance of this was examined in mice colonized with E. coli O157:H7 and given either ciprofloxacin or fosfomycin. Both antibiotics caused a reduction in fecal STEC. However, animals treated with ciprofloxacin had a marked increase in free fecal Stx, associated with death in two-thirds of the mice, whereas fosfomycin did not. Experiments that used a kanamycin-marked Stx2 prophage demonstrated that ciprofloxacin, but not fosfomycin, caused enhanced intraintestinal transfer of Stx2 prophage from one E. coli to another. These observations suggest that treatment of human STEC infection with bacteriophage-inducing antibiotics, such as fluoroquinolones, may have significant adverse clinical consequences and that fluoroquinolone antibiotics may enhance the movement of virulence factors in vivo.
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                Author and article information

                Contributors
                Role: consultant nephrologist
                Role: consultant nephrologist
                Role: professor of neurology
                Role: consultant nephrologist
                Role: medical student
                Role: consultant nephrologist
                Role: gastroenterologist
                Role: professor of nephrology
                Role: consultant nephrologist
                Role: professor of neurology and director
                Role: professor of neurology and director
                Role: professor of gastroenterology
                Role: professor of microbiology and director
                Role: consultant infectologist
                Role: medical student
                Role: professor of gastroenterology and director
                Role: consultant nephrologist
                Role: professor of gastroenterology and director
                Role: professor of nephrology and director
                Role: nephrologist and director
                Role: professor of haematology and director
                Role: consultant neurologist
                Role: registrar
                Role: professor of nephrology
                Role: doctoral student
                Role: professor of medical microbiology and assistant director
                Role: research fellow
                Role: professor of nephrology and director
                Role: professor of internal medicine and director
                Role: professor of gastroenterology and director
                Role: consultant haematologist
                Role: consultant nephrologist
                Role: medical student
                Role: professor of neurology and director
                Role: registrar
                Role: professor of nephrology and director
                Role: professor of nephrology and director
                Role: house officer
                Role: consultant nephrologist
                Role: consultant neurologist
                Role: consultant nephrologist
                Role: consultant of neuroradiology and assistant director
                Role: professor of nephrology and director
                Role: professor of nephrology
                Role: consultant of gastroenterology
                Role: consultant nephrologist
                Role: consultant nephrologist
                Role: professor of nephrology
                Role: professor of internal medicine and director
                Role: consultant haematologist
                Role: professor of nephrology and assistant director
                Role: nephrologist and director
                Role: professor of medical microbiology and director
                Role: professor of internal medicine
                Role: consultant nephrologist
                Role: professor of neurology
                Role: consultant gastroenterologist
                Role: consultant nephrologist
                Role: senior house officer
                Role: consultant gastroenterologist
                Role: professor of nephrology
                Role: consultant gastroenterologist
                Journal
                BMJ
                BMJ
                bmj
                BMJ : British Medical Journal
                BMJ Publishing Group Ltd.
                0959-8138
                1756-1833
                2012
                2012
                19 July 2012
                : 345
                : e4565
                Affiliations
                [1 ]Medical School Hannover, Hannover, Germany
                [2 ]University Hospital Schleswig-Holstein, Lübeck, Germany
                [3 ]University Hospital Schleswig-Holstein, Kiel, Germany
                [4 ]Evangelic Hospital Gilead, Bielefeld, Germany
                [5 ]Bremerhaven Hospital Reinkenheide, Bremerhaven, Germany
                [6 ]Asklepios Hospital Hamburg Altona, Hamburg
                [7 ]Hospital Hannover, Hannover, Germany
                [8 ]University Hospital Münster, Münster, Germany
                [9 ]Marienhospital Hamburg, Hamburg
                [10 ]St Vincenz Hospital, Paderborn, Germany
                [11 ]Red Cross Hospital Bremen, Bremen, Germany
                [12 ]Bremen Hospital-Mitte, Bremen, Germany
                [13 ]Asklepios Hospital Hamburg Barmbek, Hamburg
                [14 ]University of Hagen, Hagen, Germany
                [15 ]Freeman Hospital, Newcastle upon Tyne, UK
                [16 ]Helios Hospital Schwerin, Schwerin, Germany
                [17 ]Diakonissenkrankenhaus Flensburg
                [18 ]Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
                [19 ]Sahlgrenska University Hospital, Göteborg, Sweden
                [20 ]Ernst von Bergmann Clinic, Potsdam, Germany
                [21 ]Clinical Centre, University of Greifswald, Greifswald, Germany
                [22 ]Hospital Oldenburg, Oldenburg, Germany
                Author notes
                Correspondence to: J Menne Department of Nephrology and Hypertension, Medical School Hannover, Carl Neuberg Strasse 1, 30625 Hannover, Germany menne.jan@ 123456mh-hannover.de
                Article
                menj004077
                10.1136/bmj.e4565
                3400392
                22815429
                d2ca2335-0e27-4e9e-940e-2963761fe51f
                © Menne et al 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                : 6 June 2012
                Categories
                Research
                Urology
                Clinical Trials (Epidemiology)
                Epidemiologic Studies
                Immunology (Including Allergy)
                Epilepsy and Seizures
                Mechanical Ventilation
                Mechanical Ventilation
                Urological Surgery

                Medicine
                Medicine

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