Novel Anti-virulence Compounds Disrupt Exotoxin Expression in MRSA.

Hemolysins are lytic exotoxins expressed in most strains of S. aureus , but hemolytic activity varies between strains. We have previously reported several novel anti-virulence compounds that disrupt the S. aureus transcriptome, including hemolysin gene expression. This report delves further into our two lead compounds, loratadine and a structurally related brominated carbazole, and their effects on hemolysin production in MRSA. To gain understanding into how these compounds affect hemolysis, we analyzed these exotoxins at the DNA, RNA, and protein level after in vitro treatment. While lysis of red blood cells varied between strains, DNA sequence variation did not account for it. We hypothesized that our compounds would modulate gene expression of multiple hemolysins in a laboratory strain and a clinically relevant hospital-acquired strain of MRSA, both with SCC mec type II. RNA-seq analysis of differential gene expression in untreated and compound-treated cultures revealed hundreds of differentially expressed genes, with a significant enrichment in genes involved in hemolysis. The brominated carbazole and loratadine both displayed the ability to reduce hemolysis in the laboratory strain, but displayed differential activity in a hospital-acquired strain. These results corroborate gene expression studies as well as western blots of alpha hemolysin. Together, this work suggests that small molecules may alter exotoxin production in MRSA, but that the directionality and/or magnitude of the difference is likely strain-dependent.

Loratadine Combats Methicillin-Resistant Staphylococcus aureus by Modulating Virulence, Antibiotic Resistance, and Biofilm Genes.

Methicillin-resistant Staphylococcus aureus (MRSA) has evolved to become resistant to multiple classes of antibiotics. New antibiotics are costly to develop and deploy, and they have a limited effective lifespan. Antibiotic adjuvants are molecules that potentiate existing antibiotics through nontoxic mechanisms. We previously reported that loratadine, the active ingredient in Claritin, potentiates multiple cell-wall active antibiotics in vitro and disrupts biofilm formation through a hypothesized inhibition of the master regulatory kinase Stk1. Loratadine and oxacillin combined repressed the expression of key antibiotic resistance genes in the bla and mec operons. We hypothesized that additional genes involved in antibiotic resistance, biofilm formation, and other cellular pathways would be modulated when looking transcriptome-wide. To test this, we used RNA-seq to quantify transcript levels and found significant effects in gene expression, including genes controlling virulence, antibiotic resistance, metabolism, transcription (core RNA polymerase subunits and sigma factors), and translation (a plethora of genes encoding ribosomal proteins and elongation factor Tu). We further demonstrated the impacts of these transcriptional effects by investigating loratadine treatment on intracellular ATP levels, persister formation, and biofilm formation and morphology. Loratadine minimized biofilm formation in vitro and enhanced the survival of infected Caenorhabditis elegans. These pleiotropic effects and their demonstrated outcomes on MRSA virulence and survival phenotypes position loratadine as an attractive anti-infective against MRSA.

Antithrombotic use and bleeding risk in patients with atrial fibrillation: findings from a multipayer analysis.

AIMS: To analyze administrative claims data from Medicaid, Medicare and commercial insurance sources to estimate stroke risk, bleeding risk, and the use of antithrombotic treatment in patients with atrial fibrillation (AF). METHODS: Included patients were aged ≥18 years with a new or existing diagnosis of AF. Outcomes were assessed over 1 year and included stroke risk (CHADS2/CHA2DS2-VASc score), bleeding risk (ATRIA score) and anticoagulant use. RESULTS: A total of 115,906 patients with AF met inclusion criteria between six databases. Among patients with high stroke risk (CHADS2 ≥2) and low bleeding risk (ATRIA 0-3), 42-82% did not receive an antithrombotic. CONCLUSION: Levels of thromboprophylaxis for high-risk AF patients in real-world data differ significantly from current medical guidelines for stroke prevention.

National trends in advanced outpatient diagnostic imaging utilization: an analysis of the medical expenditure panel survey, 2000-2009.

BACKGROUND: Concerns have been raised regarding growth in advanced diagnostic imaging use. This study evaluated trends in national outpatient MRI/CT utilization rates during 2000-2009 and factors associated with utilization. METHODS: This retrospective database analysis used data on all respondents in the nationally representative U.S. Medical Expenditure Panel Survey (MEPS) during 2000-2009. Visits involving advanced diagnostic imaging were identified based on self-reported use of MRI or CT tests at emergency departments, office-based medical providers, and outpatient departments. The imaging utilization rate was defined as the number of outpatient visits with MRI/CT per 1,000 person-years. Results were weighted to create nationally representative estimates at the person-year level for each year and the pooled 10-year period. A multivariate logistic regression was estimated to identify predictors of imaging use. RESULTS: A total of 319,246 person-years were included in the analysis. MRI/CT utilization rates increased from 64.3 to 109.1 per 1,000 person years from 2000 to 2009, with older persons, females and Medicare enrollees having higher rates of use. Growth in imaging slowed in recent years; the average annual decline in the imaging growth rate was larger than that for all outpatient services (4.7% vs. 0.9%). The percentage of respondents with MRI/CT use (6.7% during 2000-2009) also increased at a slower rate in later years and declined during 2007-2009. The average number of MRI/CT visits among imaging users was steady at about 1.5 visits during 2000-2009. Age, female gender, White race, HMO participation, and all payer types (vs. uninsured) were significant predictors of imaging use. Compared to 2005, years 2000-2003 were associated with a significantly lower likelihood of imaging use, while years 2004-2009 were not significantly associated, suggesting a slow-down in later years. CONCLUSIONS: Growth in advanced imaging utilization appears to have slowed in recent years, a finding of potential interest to policy-makers and payers.

Rates and predictors of antipsychotic non-adherence and hospitalization in Medicaid and commercially-insured patients with schizophrenia.

OBJECTIVE: To assess rates and predictors of antipsychotic non-adherence and hospitalizations among patients with schizophrenia in separate Medicaid and commercial populations. METHODS: This retrospective analysis used the Thomson Reuters MarketScan Multi-State Medicaid and IMS LifeLink Health Plan claims databases. These analyses included patients with a diagnosis of schizophrenia (295.xx) who received a prescription for an antipsychotic between January 1, 2008, and June 30, 2009 (date of first claim in window defined as index). Patients were required to have one additional antipsychotic prescription in the 1 year following index. Rates of adherence and psychiatric and all-cause hospitalization were evaluated. Multivariate logistic regression models identified predictors of antipsychotic non-adherence and hospitalization. These analyses were not intended to compare outcomes between the Medicaid and commercial populations. RESULTS: Patients, 20,710 Medicaid and 7528 commercial, met all inclusion criteria. Both populations were ∼47% male, with a younger mean ± SD age among the Medicaid population (42.6 ± 14.1 vs 47.9 ± 17.1 years). Mean ± SD MPR in follow-up was 0.77 ± 0.25 in the Medicaid population (37.5% non-adherent) and 0.73 ± 0.27 in the commercial group (44.6% non-adherent). Rates of all-cause and psychiatric hospitalizations were 28.6% and 27.2%, respectively, among Medicaid and 29.2% and 26.3% among commercial patients. Newly starting antipsychotics and being non-adherent to therapy at baseline were both found to significantly increase the likelihood of non-adherence 12-fold in the Medicaid population (both p < 0.001) and 8-fold in the commercial population (both p < 0.001). Medicaid patients with a baseline psychiatric hospitalization had a 3-fold increased likelihood of hospitalization (p < 0.001) and commercial patients had a 2-fold increase (p < 0.001). LIMITATIONS: These two populations were not compared statistically; no conclusions as to the cause of any observed differences in outcomes can be made. CONCLUSIONS: Previous non-adherence, newly starting antipsychotic therapy, and previous hospitalization were significant predictors of non-adherence and hospitalization in Medicaid and commercial populations.

Failure of surgical and endovascular infrainguinal and iliac procedures in the management of peripheral arterial disease using data from electronic medical records.

PURPOSE: To understand rates of procedure failure among patients undergoing revascularization for peripheral arterial disease (PAD) in clinical practice. MATERIALS AND METHODS: This retrospective analysis of patients with PAD who underwent a PAD-related procedure used claims and electronic medical record data from 2005 to 2009. Procedures were grouped by type (endovascular [ie, angioplasty with/without stent, atherectomy] or surgical [ie, bypass surgery, endarterectomy, thrombectomy]) and site (ie, iliac, infrainguinal). The study assessed antiplatelet and anticoagulant agent use; procedure failure, defined as a subsequent procedure or amputation; and predictors of time to procedure failure. RESULTS: A sample of 248 patients with PAD who underwent a PAD-related procedure was identified. The population was 59% male, had a mean age of 73 years, and had a mean follow-up of 23 months. Endovascular procedures alone were performed in 37% of patients, with the remainder receiving surgery only or surgery with an endovascular procedure, and 79% of patients had an infrainguinal intervention. Antiplatelet and anticoagulant use rates after the procedure were 90% and 25%, respectively. After their initial procedure, 20% of patients required a second procedure or amputation, with an average failure time of 228 days. Patients treated with infrainguinal procedures had a significantly higher failure rate versus those treated with iliac procedures (23% vs 8%; P = .011). In multivariate analysis, patients without anticoagulant use before the procedure were at significantly lower failure risk (P = .022). CONCLUSIONS: Repeated intervention and/or major amputation after revascularization of PAD was common. Further investigation of the factors associated with procedure failure is warranted.

Lost productivity due to premature mortality in developed and emerging countries: an application to smoking cessation.

BACKGROUND: Researchers and policy makers have determined that accounting for productivity costs, or "indirect costs," may be as important as including direct medical expenditures when evaluating the societal value of health interventions. These costs are also important when estimating the global burden of disease. The estimation of indirect costs is commonly done on a country-specific basis. However, there are few studies that evaluate indirect costs across countries using a consistent methodology. METHODS: Using the human capital approach, we developed a model that estimates productivity costs as the present value of lifetime earnings (PVLE) lost due to premature mortality. Applying this methodology, the model estimates productivity costs for 29 selected countries, both developed and emerging. We also provide an illustration of how the inclusion of productivity costs contributes to an analysis of the societal burden of smoking. A sensitivity analysis is undertaken to assess productivity costs on the basis of the friction cost approach. RESULTS: PVLE estimates were higher for certain subpopulations, such as men, younger people, and people in developed countries. In the case study, productivity cost estimates from our model showed that productivity loss was a substantial share of the total cost burden of premature mortality due to smoking, accounting for over 75 % of total lifetime costs in the United States and 67 % of total lifetime costs in Brazil. Productivity costs were much lower using the friction cost approach among those of working age. CONCLUSIONS: Our PVLE model is a novel tool allowing researchers to incorporate the value of lost productivity due to premature mortality into economic analyses of treatments for diseases or health interventions. We provide PVLE estimates for a number of emerging and developed countries. Including productivity costs in a health economics study allows for a more comprehensive analysis, and, as demonstrated by our illustration, can have important effects on the results and conclusions.