The rise of antibiotic resistance and declining discovery of new antibiotics have created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. In an animal host model, SCH-79797 reduces pathogenesis of Acinetobacter baumannii, a drug-resistant Gramnegative pathogen. To characterize the MoA of SCH-79797 we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline shows that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments with other antifolates and membrane disruptors in killing MRSA persisters. Thus, SCH-79797 represents a promising lead antibiotic and suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to target challenging bacterial pathogens..

Background The treatment of patients with acute myocardial infarction (AMI) was transformed by the introduction of intensive care units (ICUs), yet we know little about how contemporary hospitals employ this resource-intensive setting and whether higher use is associated with better outcomes. Methods We identified 114,980 adult hospitalizations for AMI from 311 hospitals in the 2009–10 Premier database using codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. Hospitals were stratified into quartiles by rates of ICU admission for AMI patients. Across quartiles, we examined in-hospital risk-standardized mortality rates and usage rates of critical care therapies for these patients. Results Rates of ICU admission for AMI patients varied markedly among hospitals (median 48%, Q1 20% to Q4 71%, range 0%–98%) and there was no association with in-hospital risk-standardized mortality rates (6% all quartiles; p=0.7). However, hospitals admitting more AMI patients to the ICU were more likely to use critical care therapies overall (mechanical ventilation [from Q1 with lowest rate of ICU use to Q4 with highest rate: 13% to 16%], vasopressors/inotropes [17% to 21%], intra-aortic balloon pumps [4% to 7%], and pulmonary artery catheters [4% to 5%]; p for trend <0.05 in all comparisons). Conclusions Rates of ICU admission for patients with AMI vary substantially across hospitals and were not associated with differences in mortality, but were associated with greater use of critical care therapies. These findings suggest uncertainty about the appropriate use of this resource-intensive setting and a need to optimize ICU triage for patients who will truly benefit.

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Level V, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Post-AF total direct healthcare costs were 3 times greater than pre-AF costs. For those with a TIA, IS or MB, post-AF total direct healthcare costs increased 4.5 times from pre-AF costs; overall post-event costs in this cohort increased approximately 25% over pre-event costs. Nearly half of the events occurred within 1 month of a claim associated with an AF diagnosis. Warfarin exposure appeared to be associated with lower pmpm costs in this population.