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.

SUMMARY CDK4/6 inhibitors (CDK4/6i) are effective in breast cancer, however drug resistance is frequently encountered and poorly understood. We conducted a genomic analysis of 348 estrogen receptor-positive breast cancers treated with CDK4/6i and identified loss of function mutations affecting FAT1 and RB1 linked to drug resistance. FAT1 loss led to marked elevations in CDK6 whose suppression restored sensitivity to CDK4/6i. The induction of CDK6 was mediated by the Hippo pathway with accumulation of YAP and TAZ transcription factors on the CDK6 promoter. Genomic alterations in other Hippo pathway components were also found to promote CDK4/6i resistance. These findings uncover a tumor suppressor function of Hippo signaling in ER+ breast cancer and establish FAT1 loss as a mechanism of resistance to CDK4/6i.

Antibiotic resistance has increased markedly in gram-negative bacteria over the last two decades, and in many cases has been associated with increased mortality and healthcare costs. The adoption of genotyping and next generation whole genome sequencing of large sets of clinical bacterial isolates has greatly expanded our understanding of how antibiotic resistance develops and transmits among bacteria and between patients. Diverse mechanisms of resistance, including antibiotic degradation, antibiotic target modification, and modulation of permeability through the bacterial membrane have been demonstrated. These fundamental insights into the mechanisms of gram-negative antibiotic resistance have influenced the development of novel antibiotics and treatment practices in highly resistant infections. Here, we review the mechanisms and global epidemiology of antibiotic resistance in some of the most clinically important resistance phenotypes, including carbapenem resistant Enterobacteriaceae, extensively drug resistant (XDR) Pseudomonas aeruginosa, and XDR Acinetobacter baumannii. Understanding the resistance mechanisms and epidemiology of these pathogens is critical for the development of novel antibacterials and for individual treatment decisions, which often involve alternatives to β-lactam antibiotics.

Objectives: The role of follow-up blood cultures (FUBCs) in the management of Gram-negative bacteraemia (GNB) is poorly understood. We aimed to determine the utility of FUBCs in identifying patients with increased mortality risk. Methods: An observational study with a prospectively enrolled cohort of adult inpatients with GNB was conducted at Duke University Health System from 2002 to 2015. FUBCs were defined as blood cultures performed from 24 hours to 7 days from initial positive blood culture. Results: Among 1702 patients with GNB, 1164 (68%) had FUBCs performed. When performed, FUBCs were positive in 20% (228/1113) of cases. FUBC acquisition was associated with lower all-cause in-hospital mortality (108/538, 20%, vs. 176/1164, 15%; p 0.01) and attributable in-hospital mortality (78/538, 15%, vs. 98/1164, 8%; p < 0.0001). Propensity scoreeweighted Cox proportional hazards models revealed that obtaining FUBCs was associated with reductions in all-cause (hazard ratio (HR) 0.629; 95% confidence interval (CI), 0.511e0.772; p < 0.0001) and attributable mortality (HR 0.628; 95% CI, 0.480e0.820; p 0.0007). Positive FUBCs were associated with increased all-cause mortality (49/228, 21%, vs. 110/885, 11%; p 0.0005) and attributable mortality (27/228, 12%, vs. 61/885, 7%; p 0.01) relative to negative FUBCs. Propensity scoreeweighted Cox proportional hazards models revealed that positive FUBCs were associated with increased all-cause (HR 2.099; 95% CI, 1.567e2.811; p < 0.0001) and attributable mortality (HR 1.800; 95% CI, 1.245e2.603; p 0.002). In a calibration analysis, a scoring system accurately identified patients at high risk of positive FUBCs. Conclusions: Rates of positive FUBCs were high and identified patients at increased risk for mortality. Clinical variables can identify patients at high risk for positive FUBCs. FUBCs should be considered in the management of GNB.