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      Appropriate initial antibiotic therapy in hospitalized patients with gram-negative infections: systematic review and meta-analysis

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          Abstract

          Background

          The rapid global spread of multi-resistant bacteria and loss of antibiotic effectiveness increases the risk of initial inappropriate antibiotic therapy (IAT) and poses a serious threat to patient safety. We conducted a systematic review and meta-analysis of published studies to summarize the effect of appropriate antibiotic therapy (AAT) or IAT against gram-negative bacterial infections in the hospital setting.

          Methods

          MEDLINE, EMBASE, and Cochrane CENTRAL databases were searched until May 2014 to identify English-language studies examining use of AAT or IAT in hospitalized patients with Gram-negative pathogens. Outcomes of interest included mortality, clinical cure, cost, and length of stay. Citations and eligible full-text articles were screened in duplicate. Random effect models meta-analysis was used.

          Results

          Fifty-seven studies in 60 publications were eligible. AAT was associated with lower risk of mortality (unadjusted summary odds ratio [OR] 0.38, 95 % confidence interval [CI] 0.30-0.47, 39 studies, 5809 patients) and treatment failure (OR 0.22, 95 % CI 0.14–0.35; 3 studies, 283 patients). Conversely, IAT increased risk of mortality (unadjusted summary OR 2.66, 95 % CI 2.12–3.35; 39 studies, 5809 patients). In meta-analyses of adjusted data, AAT was associated with lower risk of mortality (adjusted summary OR 0.43, 95 % CI 0.23–0.83; 6 studies, 1409 patients). Conversely, IAT increased risk of mortality (adjusted summary OR 3.30, 95 % CI 2.42–4.49; 16 studies, 2493 patients). A limited number of studies suggested higher cost and longer hospital stay with IAT. There was considerable heterogeneity in the definition of AAT or IAT, pathogens studied, and outcomes assessed.

          Discussion

          Using a large set of studies we found that IAT is associated with a number of serious consequences,including an increased risk of hospital mortality. Infections caused by drug-resistant, Gram-negative organisms represent a considerable financial burden to healthcare systems due to the increased costs associated with the resources required to manage the infection, particularly longer hospital stays. However, there were insufficient data that evaluated AAT for the outcome of costs among patients with nosocomialGram-negative infections.

          Conclusions

          IAT in hospitalized patients with Gram-negative infections is associated with adverse outcomes. Technological advances for rapid diagnostics to facilitate AAT along with antimicrobial stewardship, surveillance, infection control, and prevention is needed.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12879-015-1123-5) contains supplementary material, which is available to authorized users.

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          Most cited references 63

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          Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment.

          Bloodstream infections (BSIs) caused by Klebsiella pneumoniae carbapenemases (KPC)-producing K. pneumoniae (KPC-KP) are associated with high mortality rates. We investigated outcomes, risk factors for mortality and impact of appropriate antimicrobial treatment in patients with BSIs caused by molecularly confirmed KPC-KP. All consecutive patients with KPC-KP BSIs between May 2008 and May 2010 were included in the study and followed-up until their discharge or death. Potential risk factors for infection mortality were examined by a case-control study. Case-patients were those who died from the BSI and control-patients those who survived. Appropriate antimicrobial therapy was defined as treatment with in vitro active antimicrobials for at least 48 h. A total of 53 patients were identified. Overall mortality was 52.8% and infection mortality was 34%. Appropriate antimicrobial therapy was administered to 35 patients; mortality due to infection occurred in 20%. All 20 patients that received combination schemes had favourable infection outcome; in contrast, seven of 15 patients given appropriate monotherapy died (p 0.001). In univariate analysis, risk factors for mortality were age (p <0.001), APACHE II score at admission and infection onset (p <0.001) and severe sepsis (p <0.001), while appropriate antimicrobial treatment (p 0.003), combinations of active antimicrobials (p 0.001), catheter-related bacteraemia (p 0.04), prior surgery (p 0.014) and other therapeutic interventions (p 0.015) were significantly associated with survival. Independent predictors of mortality were age, APACHE II score at infection onset and inappropriate antimicrobial treatment. Among them, appropriate treatment is the only modifiable independent predictor of infection outcome. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.
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            The beta-lactamase threat in Enterobacteriaceae, Pseudomonas and Acinetobacter.

            Over the past 60 years, the use of successive generations of beta-lactam antibiotics has selected successive generations of beta-lactamase enzymes, each more potent than the last. Currently, rising problems include CTX-M extended-spectrum beta-lactamases (ESBLs), plasmid-mediated AmpC beta-lactamases and KPC carbapenemases in Enterobacteriaceae, while OXA- and metallo- carbapenemases are of growing importance in Acinetobacter spp. and (less so) in other non-fermenters. Escherichia coli isolates with CTX-M ESBLs are spreading multiresistance in the community and in hospitals, while carbapenemase-producing Acinetobacter spp., mostly from intensive care, are among the most multiresistant nosocomial bacteria known and are often susceptible only to polymyxins and, potentially, tigecycline. This review discusses the epidemiology and microbiology of these resistance problems, along with possible solutions.
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              Pseudomonas aeruginosa bloodstream infection: importance of appropriate initial antimicrobial treatment.

              Pseudomonas aeruginosa bloodstream infection is a serious infection with significant patient mortality and health-care costs. Nevertheless, the relationship between initial appropriate antimicrobial treatment and clinical outcomes is not well established. This study was a retrospective cohort analysis employing automated patient medical records and the pharmacy database at Barnes-Jewish Hospital. Three hundred five patients with P. aeruginosa bloodstream infection were identified over a 6-year period (January 1997 through December 2002). Sixty-four (21.0%) patients died during hospitalization. Hospital mortality was statistically greater for patients receiving inappropriate initial antimicrobial treatment (n = 75) compared to appropriate initial treatment (n = 230) (30.7% versus 17.8%; P = 0.018). Multiple logistic regression analysis identified inappropriate initial antimicrobial treatment (adjusted odds ratio [AOR], 2.04; 95% confidence interval [CI], 1.42 to 2.92; P = 0.048), respiratory failure (AOR, 5.18; 95% CI, 3.30 to 8.13; P < 0.001), and circulatory shock (AOR, 4.00; 95% CI, 2.71 to 5.91; P < 0.001) as independent determinants of hospital mortality. Appropriate initial antimicrobial treatment was administered statistically more often among patients receiving empirical combination antimicrobial treatment for gram-negative bacteria compared to empirical monotherapy (79.4% versus 65.5%; P = 0.011). Inappropriate initial empirical antimicrobial treatment is associated with greater hospital mortality among patients with P. aeruginosa bloodstream infection. Inappropriate antimicrobial treatment of P. aeruginosa bloodstream infections may be minimized by increased use of combination antimicrobial treatment until susceptibility results become known.
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                Author and article information

                Contributors
                graman@tuftsmedicalcenter.org
                eavendano@tuftsmedicalcenter.org
                samantha.berger@tufts.edu
                vandana.menon@gmail.com
                Journal
                BMC Infect Dis
                BMC Infect. Dis
                BMC Infectious Diseases
                BioMed Central (London )
                1471-2334
                30 September 2015
                30 September 2015
                2015
                : 15
                Affiliations
                [ ]Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Box 63, 800 Washington Street, Boston, MA 02111 USA
                [ ]Tufts University School of Medicine, 145 Harrison Avenue, Boston, MA 02111 USA
                [ ]Tufts University Friedman School of Nutrition Science and Policy, 150 Harrison Avenue, Boston, MA 02111 USA
                [ ]Currently employed at Baxalta and a former employee of Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, MA 02421 USA
                Article
                1123
                10.1186/s12879-015-1123-5
                4589179
                26423743
                © Raman et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                © The Author(s) 2015

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