SUMMARY Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections. It is a leading cause of bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. This review comprehensively covers the epidemiology, pathophysiology, clinical manifestations, and management of each of these clinical entities. The past 2 decades have witnessed two clear shifts in the epidemiology of S. aureus infections: first, a growing number of health care-associated infections, particularly seen in infective endocarditis and prosthetic device infections, and second, an epidemic of community-associated skin and soft tissue infections driven by strains with certain virulence factors and resistance to β-lactam antibiotics. In reviewing the literature to support management strategies for these clinical manifestations, we also highlight the paucity of high-quality evidence for many key clinical questions.

Background— Infective endocarditis is a potentially lethal disease that has undergone major changes in both host and pathogen. The epidemiology of infective endocarditis has become more complex with today’s myriad healthcare-associated factors that predispose to infection. Moreover, changes in pathogen prevalence, in particular a more common staphylococcal origin, have affected outcomes, which have not improved despite medical and surgical advances. Methods and Results— This statement updates the 2005 iteration, both of which were developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It includes an evidence-based system for diagnostic and treatment recommendations used by the American College of Cardiology and the American Heart Association for treatment recommendations. Conclusions— Infective endocarditis is a complex disease, and patients with this disease generally require management by a team of physicians and allied health providers with a variety of areas of expertise. The recommendations provided in this document are intended to assist in the management of this uncommon but potentially deadly infection. The clinical variability and complexity in infective endocarditis, however, dictate that these recommendations be used to support and not supplant decisions in individual patient management.

Daptomycin (6 mg per kilogram daily) is not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis. (ClinicalTrials.gov number, NCT00093067 [ClinicalTrials.gov].).

First identified in purulent fluid from a leg abscess by Ogston in the 1880s and formally isolated by Rosenbach not long after, Staphylococcus aureus is well adapted to its human host and the health-care environment 1. S. aureus is both a frequent commensal and a leading cause of endocarditis, bacteraemia, osteomyelitis and skin and soft tissue infections. With the rise of hospital-based medicine, S. aureus quickly became a leading cause of healthcare-associated infections as well. Penicillin offered short-lived relief: resistance arose in the 1940s, mediated by the β-lactamase gene blaZ. The first semi-synthetic anti-staphylococcal penicillins were developed around 1960 and methicillin-resistant S. aureus (MRSA) was observed within 1 year of their first clinical use. In fact, genomic evidence suggests that methicillin resistance even preceded the first clinical use of anti-staphylococcal penicillins 2. Methicillin resistance is mediated by mecA and acquired by horizontal transfer of a mobile genetic element designated staphylococcal cassette chromosome mec (SCCmec) 3. The gene mecA encodes penicillinbinding protein 2a (PBP2a), an enzyme responsible for crosslinking the peptidoglycans in the bacterial cell wall. PBP2a has a low affinity for β-lactams, resulting in resistance to this entire class of antibiotics 4. MRSA was first observed among clinical isolates from patients hospitalized in the 1960s, but since the 1990s it has spread rapidly in the community 5. Although MRSA infection occurs globally, there is no single pandemic strain. Instead, MRSA tends to occur in waves of infection, often characterized by the serial emergence of predominant strains. Recent examples of emergent MRSA strains include the health-careassociated MRSA (HA-MRSA) clonal complex 30 (CC30) in North America and Europe, community-associated MRSA (CA-MRSA) USA300 in North America and livestock-associated MRSA (including ST398) and ST93 in Australia 6-9. Rates of both CA-MRSA and HA-MRSA appear to be declining in several regions, a trend first noted with HA-MRSA in the United Kingdom 10,11. The reason for the serial rise and fall of specific strain types remains poorly understood. MRSA colonization increases the risk of infection, and infecting strains match colonizing strains in as many as 50-80% of cases 12,13. Nearly any item in contact with skin can serve as a fomite in MRSA transmission, from white coats and ties to pens and mobile telephones. Colonization can persist for long periods of time. MRSA may also persist within the home environment, complicating attempts at eradication 14. At the same time, colonization is not static, as strains have been found to evolve and even to be replaced within the same host 15. Endocarditis An infection of the interior heart structures or valves. Osteomyelitis An infection involving bone. Methicillin An anti-staphylococcal penicillin. Fomite An object or material capable of carrying or transmitting infection.

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Data for 479 patients were analyzed to assess the impact of methicillin resistance on the outcomes of patients with Staphylococcus aureus surgical site infections (SSIs). Patients infected with methicillin-resistant S. aureus (MRSA) had a greater 90-day mortality rate than did patients infected with methicillin-susceptible S. aureus (MSSA; adjusted odds ratio, 3.4; 95% confidence interval, 1. 5-7.2). Patients infected with MRSA had a greater duration of hospitalization after infection (median additional days, 5;), although this was not significant P ! .001 on multivariate analysis ( ). Median hospital charges were $29,455 for control subjects, $52,791 for P p .11 patients with MSSA SSI, and $92,363 for patients with MRSA SSI ( for all group comparisons). Patients P ! .001 with MRSA SSI had a 1.19-fold increase in hospital charges ( ) and had mean attributable excess charges P p .03 of $13,901 per SSI compared with patients who had MSSA SSIs. Methicillin resistance is independently associated with increased mortality and hospital charges among patients with S. aureus SSI.Although methicillin-resistant Staphylococcus aureus (MRSA) is an increasingly common pathogen, the independent contribution of methicillin resistance to the outcomes for patients with S. aureus infection is unclear because patients who develop MRSA infections are typically older and sicker than are patients who develop methicillin-susceptible S. aureus (MSSA) infection. Surgical site infection (SSI) complicates 2%-5% of all

Background-Despite advances in medical, surgical, and critical care interventions, infective endocarditis remains a disease that is associated with considerable morbidity and mortality. The continuing evolution of antimicrobial resistance among common pathogens that cause infective endocarditis creates additional therapeutic issues for physicians to manage in this potentially life-threatening illness. Methods and Results-This work represents the third iteration of an infective endocarditis "treatment" document developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It updates recommendations for diagnosis, treatment, and management of complications of infective endocarditis. A multidisciplinary committee of experts drafted this document to assist physicians in the evolving care of patients with infective endocarditis in the new millennium. This extensive document is accompanied by an executive summary that covers the key points of the diagnosis, antimicrobial therapy, and management of infective endocarditis. For the first time, an evidence-based scoring system that is used by the American College of Cardiology and the American Heart Association was applied to treatment recommendations. Tables also have been included that provide input on the use of echocardiography during diagnosis and treatment of infective endocarditis, evaluation and treatment of culture-negative endocarditis, and short-term and long-term management of patients during and after completion of antimicrobial treatment. To assist physicians who care for children, pediatric dosing was added to each treatment regimen. Conclusions-The recommendations outlined in this update should assist physicians in all aspects of patient care in the diagnosis, medical and surgical treatment, and follow-up of infective endocarditis, as well as management of associated complications. Clinical variability and complexity in infective endocarditis, however, dictate that these guidelines be used to support and not supplant physician-directed decisions in individual patient management. (Circulation. 2005; 111:e394-e433.)

Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features, and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would die differed markedly from those who would survive. The different profiles of proteins and metabolites clustered into fatty acid transport and β-oxidation, gluconeogenesis and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of seven metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.