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      Preventing Staphylococcus aureus Sepsis through the Inhibition of Its Agglutination in Blood

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          Abstract

          Staphylococcus aureus infection is a frequent cause of sepsis in humans, a disease associated with high mortality and without specific intervention. When suspended in human or animal plasma, staphylococci are known to agglutinate, however the bacterial factors responsible for agglutination and their possible contribution to disease pathogenesis have not yet been revealed. Using a mouse model for S. aureus sepsis, we report here that staphylococcal agglutination in blood was associated with a lethal outcome of this disease. Three secreted products of staphylococci - coagulase (Coa), von Willebrand factor binding protein (vWbp) and clumping factor (ClfA) – were required for agglutination. Coa and vWbp activate prothrombin to cleave fibrinogen, whereas ClfA allowed staphylococci to associate with the resulting fibrin cables. All three virulence genes promoted the formation of thromboembolic lesions in heart tissues. S. aureus agglutination could be disrupted and the lethal outcome of sepsis could be prevented by combining dabigatran-etexilate treatment, which blocked Coa and vWbp activity, with antibodies specific for ClfA. Together these results suggest that the combined administration of direct thrombin inhibitors and ClfA-antibodies that block S. aureus agglutination with fibrin may be useful for the prevention of staphylococcal sepsis in humans.

          Author Summary

          Staphylococcus aureus secretes factors that perturb blood coagulation in infected hosts. We report here that three bacterial products – coagulase (Coa), von Willebrand factor binding protein (vWbp) and clumping factor (ClfA) - act together and promote agglutination, the association of staphylococci with polymerized fibrin cables. Staphylococcal agglutination was associated with thromboembolic lesions in heart tissues and a lethal outcome of S. aureus sepsis in mice. Inhibition of Coa and vWbp with direct thrombin inhibitors, drugs already approved for the prevention of stroke, as well as passive transfer of antibodies specific for Coa, vWbp and ClfA could prevent the pathogenesis of S. aureus sepsis. These results suggest new preventive and/or therapeutic strategies that may improve the outcome of S. aureus sepsis in humans, a disease that is otherwise associated with high mortality.

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          Most cited references 57

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          Invasive methicillin-resistant Staphylococcus aureus infections in the United States.

          As the epidemiology of infections with methicillin-resistant Staphylococcus aureus (MRSA) changes, accurate information on the scope and magnitude of MRSA infections in the US population is needed. To describe the incidence and distribution of invasive MRSA disease in 9 US communities and to estimate the burden of invasive MRSA infections in the United States in 2005. Active, population-based surveillance for invasive MRSA in 9 sites participating in the Active Bacterial Core surveillance (ABCs)/Emerging Infections Program Network from July 2004 through December 2005. Reports of MRSA were investigated and classified as either health care-associated (either hospital-onset or community-onset) or community-associated (patients without established health care risk factors for MRSA). Incidence rates and estimated number of invasive MRSA infections and in-hospital deaths among patients with MRSA in the United States in 2005; interval estimates of incidence excluding 1 site that appeared to be an outlier with the highest incidence; molecular characterization of infecting strains. There were 8987 observed cases of invasive MRSA reported during the surveillance period. Most MRSA infections were health care-associated: 5250 (58.4%) were community-onset infections, 2389 (26.6%) were hospital-onset infections; 1234 (13.7%) were community-associated infections, and 114 (1.3%) could not be classified. In 2005, the standardized incidence rate of invasive MRSA was 31.8 per 100,000 (interval estimate, 24.4-35.2). Incidence rates were highest among persons 65 years and older (127.7 per 100,000; interval estimate, 92.6-156.9), blacks (66.5 per 100,000; interval estimate, 43.5-63.1), and males (37.5 per 100,000; interval estimate, 26.8-39.5). There were 1598 in-hospital deaths among patients with MRSA infection during the surveillance period. In 2005, the standardized mortality rate was 6.3 per 100,000 (interval estimate, 3.3-7.5). Molecular testing identified strains historically associated with community-associated disease outbreaks recovered from cultures in both hospital-onset and community-onset health care-associated infections in all surveillance areas. Invasive MRSA infection affects certain populations disproportionately. It is a major public health problem primarily related to health care but no longer confined to intensive care units, acute care hospitals, or any health care institution.
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            Waves of resistance: Staphylococcus aureus in the antibiotic era.

            Staphylococcus aureus is notorious for its ability to become resistant to antibiotics. Infections that are caused by antibiotic-resistant strains often occur in epidemic waves that are initiated by one or a few successful clones. Methicillin-resistant S. aureus (MRSA) features prominently in these epidemics. Historically associated with hospitals and other health care settings, MRSA has now emerged as a widespread cause of community infections. Community or community-associated MRSA (CA-MRSA) can spread rapidly among healthy individuals. Outbreaks of CA-MRSA infections have been reported worldwide, and CA-MRSA strains are now epidemic in the United States. Here, we review the molecular epidemiology of the epidemic waves of penicillin- and methicillin-resistant strains of S. aureus that have occurred since 1940, with a focus on the clinical and molecular epidemiology of CA-MRSA.
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              Community-associated meticillin-resistant Staphylococcus aureus.

              Meticillin-resistant Staphylococcus aureus (MRSA) is endemic in hospitals worldwide, and causes substantial morbidity and mortality. Health-care-associated MRSA infections arise in individuals with predisposing risk factors, such as surgery or presence of an indwelling medical device. By contrast, many community-associated MRSA (CA-MRSA) infections arise in otherwise healthy individuals who do not have such risk factors. Additionally, CA-MRSA infections are epidemic in some countries. These features suggest that CA-MRSA strains are more virulent and transmissible than are traditional hospital-associated MRSA strains. The restricted treatment options for CA-MRSA infections compound the effect of enhanced virulence and transmission. Although progress has been made towards understanding emergence of CA-MRSA, virulence, and treatment of infections, our knowledge remains incomplete. Here we review the most up-to-date knowledge and provide a perspective for the future prophylaxis or new treatments for CA-MRSA infections. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                October 2011
                October 2011
                20 October 2011
                : 7
                : 10
                Affiliations
                Department of Microbiology, University of Chicago, Chicago, Illinois, United States of America
                University of California, San Francisco, United States of America
                Author notes

                Conceived and designed the experiments: MM HKK ACD APAH DMM OS. Performed the experiments: MM HKK APAH ACD. Analyzed the data: MM HKK ACD APAH DMM OS. Contributed reagents/materials/analysis tools: MM HKK ACD APAH. Wrote the paper: MM ACD DMM OS.

                Article
                PPATHOGENS-D-11-01024
                10.1371/journal.ppat.1002307
                3197598
                22028651
                McAdow et al. 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.
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Biochemistry
                Genetics
                Microbiology
                Medicine
                Critical Care and Emergency Medicine
                Drugs and Devices
                Global Health
                Hematology
                Infectious Diseases
                Public Health

                Infectious disease & Microbiology

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