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      Risk Factors for Recurrence, Complications and Mortality in Clostridium difficile Infection: A Systematic Review

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          Abstract

          Background

          Clostridium difficile infection (CDI) can lead to complications, recurrence, and death. Numerous studies have assessed risk factors for these unfavourable outcomes, but systematic reviews or meta-analyses published so far were limited in scope or in quality.

          Methods

          A systematic review was completed according to PRISMA guidelines. An electronic search in five databases was performed. Studies published until October 2013 were included if risk factors for at least one CDI outcome were assessed with multivariate analyses.

          Results

          68 studies were included: 24 assessed risk factors for recurrence, 18 for complicated CDI, 8 for treatment failure, and 30 for mortality. Most studies accounted for mortality in the definition of complicated CDI. Important variables were inconsistently reported, such as previous episodes and use of antibiotics. Substantial heterogeneity and methodological limitations were noted, mainly in the sample size, the definition of the outcomes and periods of follow-up, precluding a meta-analysis. Older age, use of antibiotics after diagnosis, use of proton pump inhibitors, and strain type were the most frequent risk factors for recurrence. Older age, leucocytosis, renal failure and co-morbidities were frequent risk factors for complicated CDI. When considered alone, mortality was associated with age, co-morbidities, hypo-albuminemia, leucocytosis, acute renal failure, and infection with ribotype 027.

          Conclusion

          Laboratory parameters currently used in European and American guidelines to define patients at risk of a complicated CDI are adequate. Strategies for the management of CDI should be tailored according to the age of the patient, biological markers of severity, and underlying co-morbidities.

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          Most cited references68

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          Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity.

          Recent reports suggest that Clostridium difficile colitis may be evolving into a more severe disease. During the second half of 2002 we noted an increase in the number of patients with severe C. difficile-associated diarrhea (CDAD) in our institution. We describe cases of CDAD at our institution over a 13-year period and investigate changes in illness severity. We undertook a retrospective chart review of all cases of CDAD diagnosed at the Centre hospitalier universitaire de Sherbrooke from Jan. 1, 1991, to Dec. 31, 2003. Because the hospital serves a well-defined population of Quebec, we were also able to calculate population-based incidence during this period. We abstracted data on individual patients from patient charts and from hospital and pharmacy computer databases. We defined cases of CDAD as having a positive C. difficile cytotoxicity assay result, or endoscopic or histopathological evidence of pseudomembranous colitis. A case was considered complicated if one or more of the following was observed: megacolon, perforation, colectomy, shock requiring vasopressor therapy, or death within 30 days after diagnosis. A total of 1721 cases of CDAD were diagnosed during the study period. The incidence increased from 35.6 per 100,000 population in 1991 to 156.3 per 100,000 in 2003; among patients aged 65 years or more, it increased from 102.0 to 866.5 per 100,000. The proportion of cases that were complicated increased from 7.1% (12/169) in 1991-1992 to 18.2% (71/390) in 2003 (p < 0.001), and the proportion of patients who died within 30 days after diagnosis increased from 4.7% (8/169) in 1991-1992 to 13.8% (54/390) in 2003 (p < 0.001). A high leukocyte count (20.0 small ha, Cyrillic 10(9)/L or greater) and an elevated creatinine level (200 micromol/L or greater) were strongly associated with adverse outcomes: in 2003, 45 (40.9%) of 110 patients with a high leukocyte count or creatinine level, or both, had complicated CDAD and 28 (25.5%) died within 30 days after diagnosis. After adjustment for age and other confounding factors, patients initially given oral vancomycin therapy had a risk of progression to complicated CDAD that was 79% lower than the risk among patients initially treated with metronidazole (adjusted odds ratio 0.2, 95% confidence interval 0.06-0.8, p = 0.02). An epidemic of CDAD with an increased case-fatality rate has had important consequences on the elderly population of our region. Our observational data suggest that the equivalence of vancomycin and metronidazole in the treatment of CDAD needs to be questioned.
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            Treatment with monoclonal antibodies against Clostridium difficile toxins.

            New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection. We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo. Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P<0.001). The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P=0.006). The mean duration of the initial hospitalization for inpatients did not differ significantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P=0.09). The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298.) 2010 Massachusetts Medical Society
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              Clinical prediction rules. A review and suggested modifications of methodological standards.

              Clinical prediction rules are decision-making tools for clinicians, containing variables from the history, physical examination, or simple diagnostic tests. To review the quality of recently published clinical prediction rules and to suggest methodological standards for their development and evaluation. Four general medical journals were manually searched for clinical prediction rules published from 1991 through 1994. Four hundred sixty potentially eligible reports were identified, of which 30 were clinical prediction rules eligible for study. Most methodological standards could only be evaluated in 29 studies. Two investigators independently evaluated the quality of each report using a standard data sheet. Disagreements were resolved by consensus. The mathematical technique was used to develop the rule, and the results of the rule were described in 100% (29/29) of the reports. All the rules but 1 (97% [28/29]) were felt to be clinically sensible. The outcomes and predictive variables were clearly defined in 83% (24/29) and 59% (17/29) of the reports, respectively. Blind assessment of outcomes and predictive variables occurred in 41% (12/29) and 79% (23/29) of the reports, respectively, and the rules were prospectively validated in 79% (11/14). Reproducibility of predictive variables was assessed in only 3% (1/29) of the reports, and the effect of the rule on clinical use was prospectively measured in only 3% (1/30). Forty-one percent (12/29) of the rules were felt to be easy to use. Although clinical prediction rules comply with some methodological criteria, for other criteria, better compliance is needed.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                4 June 2014
                : 9
                : 6
                : e98400
                Affiliations
                [1]Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada
                Universidad Andres Bello, Chile
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CNAC JP LV. Performed the experiments: CNAC SS LV. Analyzed the data: CNAC JP SS LV. Contributed reagents/materials/analysis tools: CNAC SS. Wrote the paper: CNAC JP SS LV.

                Article
                PONE-D-14-11662
                10.1371/journal.pone.0098400
                4045753
                24897375
                044a83fe-957a-46dc-baca-6d6c0213f699
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 14 March 2014
                : 1 May 2014
                Page count
                Pages: 14
                Funding
                These authors have no support or funding to report.
                Categories
                Research Article
                Medicine and Health Sciences
                Epidemiology
                Infectious Disease Epidemiology
                Infectious Diseases
                Healthcare-Associated Infections
                Nosocomial Infections
                Bacterial Diseases
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. Published studies.

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