Structure of grepafloxacin relative to activity and safety profile

A comparison of the structure of ciprofloxacin and grepafloxacin shows that the two compounds are similar, with two exceptions: grepafloxacin has a methyl group at the 5 position and a methyl group attached to the 7-piperazinyl substituent. At the 1 position, both compounds have a cyclopropyl group, which is important for potency, but limits anaerobic activity. The methylpiperazine at position 7 in grepafloxacin is associated with its enhanced Gram-positive activity and long half-life. The methyl group at R5 is also thought to enhance Gram-positive activity. Ciprofloxacin's piperazine group at the 7 position is associated with good Gram-negative activity. Grepafloxacin's Gram-negative activity is comparable to that of ciprofloxacin's against Haemophilus influenzae, Moraxella catarrhalis and enteric Gram-negative bacilli.Studies of resistance development to fluoroquinolones suggest that grepafloxacin is associated with a reduced selection of resistance in Staphylococcus aureus, which is possibly related to the inhibition or avoidance of efflux transport by NorA

Clinical Importance and Epidemiology of Quinolone Resistance

The quinolone class of antimicrobial agents is one of most widely used classes of antimicrobial agents in outpatient and inpatient treatment. However, quinolone resistance in gram-positive and gram-negative bacteria has emerged and increased globally. This resistance limits the usefulness of quinolones in clinical practice. The review summarizes mechanisms of quinolone resistance and its epidemiology and implications in the most common clinical settings, urinary tract infections, respiratory tract infections, intraabdominal infections, skin and skin structure infections, and sexually transmitted diseases

Pseudomoduli Dark Matter

We point out that pseudomoduli -- tree-level flat directions that often accompany dynamical supersymmetry breaking -- can be natural candidates for TeV-scale dark matter in models of gauge mediation. The idea is general and can be applied to different dark matter scenarios, including (but not limited to) those of potential relevance to recent cosmic ray anomalies. We describe the requirements for a viable model of pseudomoduli dark matter, and we analyze two example models to illustrate the general mechanism -- one where the pseudomoduli carry Higgsino-like quantum numbers, and another where they are SM singlets but are charged under a hidden-sector $U(1)'$ gauge group.Comment: 20 pages, refs adde

Natural history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE): a systematic review

Background: No published systematic reviews have assessed the natural history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE). Time to clearance of colonization has important implications for patient care and infection control policy. Methods: We performed parallel searches in OVID Medline for studies that reported the time to documented clearance of MRSA and VRE colonization in the absence of treatment, published between January 1990 and July 2012. Results: For MRSA, we screened 982 articles, identified 16 eligible studies (13 observational studies and 3 randomized controlled trials), for a total of 1,804 non-duplicated subjects. For VRE, we screened 284 articles, identified 13 eligible studies (12 observational studies and 1 randomized controlled trial), for a total of 1,936 non-duplicated subjects. Studies reported varying definitions of clearance of colonization; no study reported time of initial colonization. Studies varied in the frequency of sampling, assays used for sampling, and follow-up period. The median duration of total follow-up was 38 weeks for MRSA and 25 weeks for VRE. Based on pooled analyses, the model-estimated median time to clearance was 88 weeks after documented colonization for MRSA-colonized patients and 26 weeks for VRE-colonized patients. In a secondary analysis, clearance rates for MRSA and VRE were compared by restricting the duration of follow-up for the MRSA studies to the maximum observed time point for VRE studies (43 weeks). With this restriction, the model-fitted median time to documented clearance for MRSA would occur at 41 weeks after documented colonization, demonstrating the sensitivity of the pooled estimate to length of study follow-up. Conclusions: Few available studies report the natural history of MRSA and VRE colonization. Lack of a consistent definition of clearance, uncertainty regarding the time of initial colonization, variation in frequency of sampling for persistent colonization, assays employed and variation in duration of follow-up are limitations of the existing published literature. The heterogeneity of study characteristics limits interpretation of pooled estimates of time to clearance, however, studies included in this review suggest an increase in documented clearance over time, a result which is sensitive to duration of follow-up

Infrared Properties of High Redshift and X-ray Selected AGN Samples

The NASA/ISO Key Project on active galactic nuclei (AGN) seeks to better understand the broad-band spectral energy distributions (SEDs) of these sources from radio to X-rays, with particular emphasis on infrared properties. The ISO sample includes a wide variety of AGN types and spans a large redshift range. Two subsamples are considered herein: 8 high-redshift (1 < z < 4.7) quasars; and 22 hard X-ray selected sources. The X-ray selected AGN show a wide range of IR continuum shapes, extending to cooler colors than the optical/radio sample of Elvis et al. (1994). Where a far-IR turnover is clearly observed, the slopes are < 2.5 in all but one case so that non-thermal emission remains a possibility. The highest redshift quasars show extremely strong, hot IR continua requiring ~ 100 solar masses of 500 - 1000 Kelvin dust with ~ 100 times weaker optical emission. Possible explanations for these unusual properties include: reflection of the optical light from material above/below a torus; strong obscuration of the optical continuum; or an intrinsic deficit of optical emission.Comment: 8 pages, 3 figures (2 color), to be published in the Springer Lecture Notes of Physics Series as part of the proceedings for "ISO Surveys of a Dusty Universe," a workshop held at Ringberg Castle, Germany, November 8 - 12, 1999. Requires latex style files for this series: cl2emult.cls, cropmark.sty, lnp.sty, sprmindx.sty, subeqnar.sty (included with submission

Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

BACKGROUND: Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018

Gram-Negative Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group

Antimicrobial resistance in pathogenic gram-negative bacteria is one of the most pressing challenges in the field of infectious diseases and is one of 4 key areas of unmet medical need identified by the Antibacterial Resistance Leadership Group (ARLG). The mission of the Gram-Negative Committee is to advance our knowledge of these challenging infections and implement studies to improve patient outcomes. Studies have fallen primarily into 2 broad categories: prospective cohort studies and interventional trials. Among the observational studies, CRACKLE (Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae and Other Enterobacteriaceae) has contributed seminal multicenter data describing risk factors and clinical outcomes of carbapenem-resistant Enterobacteriaceae (CRE) in sentinel US hospitals. Building on this success, CRACKLE II will expand the network to hospitals across the United States and Colombia. Similar protocols have been proposed to include Acinetobacter baumannii and Pseudomonas aeruginosa (SNAP and POP studies). In addition, the CREST study (Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplant Patients) has provided pivotal data on extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and CRE carriage among solid organ transplant recipients to inform management of this vulnerable patient population. Two clinical trials to define novel ways of using an existing antibiotic, fosfomycin, to treat ESBL-producing Enterobacteriaceae (one that has completed enrollment and the other in late protocol development) will determine the clinical efficacy of fosfomycin as step-down oral therapy to treat complicated urinary tract infections. Additional clinical studies and trials using immunotherapeutic or newly approved agents are also in the planning stage, with the main goals of generating actionable data that will inform clinical decision making and facilitate development of new treatment options for highly resistant gram-negative bacterial infections