Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research

Abstract

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.

Molecular epidemiology and virulence factors of methicillin‐resistant Staphylococcus aureus isolated from patients with bacteremia

“…Methicillin‐resistant Staphylococcus aureus causes various diseases such as skin and soft tissue infections, endocarditis, and bone and joint infections . Among these infections, MRSA bacteremia (MRSAB) is one of the most common problems because of the associated high mortality rate.…”

Constructing and deconstructing the bacterial cell wall

“…S. aureus is a bacterial pathogen of humans and livestock. It is encountered as a β‐lactam‐susceptible strain (referred to customarily as methicillin‐susceptible S. aureus , MSSA) and as β‐lactam‐resistant strains (MRSA, encountered as a variety of strains) . Here, methicillin refers to a specific second‐generation penicillin that was developed decades ago as especially active against MSSA, as a result of its stability to the hydrolytic deactivation of its β‐lactam substructure (in contrast to first‐generation penicillins) as catalyzed by a plasmid‐encoded β‐lactamase (BlaZ).…”

“…MRSA are resistant to all but the most recent β‐lactams. Accordingly, their problematic chemotherapy requires an oxazolidinone (linezolid), one of the newest β‐lactams, or older drugs (such as daptomycin or vancomycin) whose clinical development was renewed in response to the need for anti‐MRSA agents . Resistance to each of these clinically‐used antibiotics is encountered.…”

Risk stratification biomarkers for Staphylococcus aureus bacteraemia

“…Mortality rates for patients with Staphylococcus aureus bacteraemia (SAB) largely remain unchanged despite significant advances in clinical management, with new antibiotic therapies and rapid diagnostics available in recent decades. Significant heterogeneity in the clinical course of patients with SAB despite appropriate antibiotic therapy suggests that differential host immune response may contribute to adverse patient outcomes . However, critical determinants of immune evasion in patients with SAB remain poorly understood and connections between the immune response and microbiological failure are lacking.…”

“…Significant heterogeneity in the clinical course of patients with SAB despite appropriate antibiotic therapy suggests that differential host immune response may contribute to adverse patient outcomes. [1][2][3] However, critical determinants of immune evasion in patients with SAB remain poorly understood and connections between the immune response and microbiological failure are lacking. Previous studies identified several candidate innate immunity biomarkers that were independently associated with mortality and prolonged SAB, supporting the utility of biomarkers to distinguish patients prone to developing severe disease.…”