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.

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.

Infective endocarditis (IE) is a rare, life-threatening disease that has long-lasting effects even among patients who survive and are cured. IE disproportionately affects those with underlying structural heart disease and is increasingly associated with healthcare contact, particularly in patients who have intravascular prosthetic material. In the setting of bacteraemia with a pathogenic organism, an infected vegetation may form as the end result of complex interactions between invading microorganisms and the host immune system. Once established, IE can involve almost any organ system in the body. The diagnosis of IE may be difficult to establish and a strategy that combines clinical, microbiological and echocardiography results has been codified in the modified Duke criteria. In cases of blood culture-negative IE, the diagnosis may be especially challenging and novel microbiological and imaging techniques have been developed to establish its presence. Once diagnosed, IE is best managed by a multidisciplinary team with expertise in infectious diseases, cardiology and cardiac surgery. Antibiotic prophylaxis for the prevention of IE remains controversial. Efforts to develop a vaccine targeting common bacterial causes of IE are ongoing, but have not yet yielded a commercially available product.

Importance Several management strategies may improve outcomes in patients with Staphylococcus aureus bacteremia (SAB). The strength of evidence supporting these management strategies, however, varies widely. Objective To perform a systematic review of the evidence for two unresolved questions involving management strategies for SAB: 1) is transesophageal echocardiography (TEE) necessary in all cases of SAB; and 2) what is the optimal antibiotic therapy for methicillin resistant Staphylococcus aureus (MRSA) bacteremia? Evidence acquisition A PubMed search from inception through May 2014 was performed to find studies that addressed the role of TEE in SAB. A second search of PubMed, EMBASE, and The Cochrane Library from 1/1/1990 to 5/28/2014 was performed to find studies that addressed antibiotic treatment of MRSA bacteremia. Studies that reported outcomes of systemic antibiotic therapy for MRSA bacteremia were included. All searches were augmented by review of bibliographic references from included studies. The quality of evidence was assessed using the GRADE system by consensus of independent evaluations by at least two authors. Results In 9 studies with a total of 3513 patients, use of TEE was associated with higher rates of diagnosis of endocarditis (14–25%) when compared with TTE (2–14%). Five studies proposed criteria to identify patients in whom TEE might safely be avoided. Only one high-quality trial of antibiotic therapy for MRSA bacteremia was identified from the 83 studies considered. Conclusions and relevance Most contemporary management strategies for SAB are based upon low quality evidence. TEE is indicated in most patients with SAB. It may be possible to identify a subset of SAB patients for whom TEE can be safely avoided. Vancomycin and daptomycin are the first-line antibiotic choices for MRSA bacteremia. Well-designed studies to address the management of SAB are desperately needed.