The relationship between vancomycin tolerance and clinical outcomes in patients with Staphylococcus aureus bacteremia

Background: Treatment failure is increasingly common in Staphylococcus aureus bacteremia (SAB). Vancomycin tolerance may be playing a role in clinical outcomes in SAB that has yet to be fully explored. Methods: This was a single-center retrospective cohort study of 166 patients (September 2012 - January 2014) evaluating the relationship between vancomycin tolerance and clinical failure in SAB. Vancomycin minimum inhibitory concentration (MIC) was determined by broth microdilution and Etest. Vancomycin tolerance was defined as a vancomycin minimum bactericidal concentration (MBC)/MIC greater than or equal to 32. Univariable and multivariable analyses were conducted to determine the relationship between vancomycin tolerance and clinical failure after adjusting for other factors. Results: Of the 166 patients evaluated, 26.5% had vancomycin tolerant clinical isolates. Tolerance to vancomycin was more common in methicillin-susceptible S. aureus bacteremia (MSSA-B) than methicillin-resistant S. aureus bacteremia (MRSA-B; n=29/101 [28.7%] vs. n=15/65 [23.1%]), although not significantly (P=0.422). Clinical failure was frequently observed (50% overall). Elevated vancomycin MIC by Etest (greater than or equal to 1.5 mcg/mL) was not associated with clinical failure (P=0.50). Vancomycin tolerance was significantly associated with SAB clinical failure in univariable analysis (P=0.014). This relationship persisted even when adjusting for other factors in multivariable analysis (adjusted odds ratio [AOR], 2.70; 95% confidence interval [CI], 1.27-5.70; P=0.010). Conclusions: Vancomycin tolerance is a clinically significant predictor of clinical failure in SAB independent of methicillin susceptibility and antibiotic choice. Future research is needed to determine optimal treatment of vancomycin tolerant SAB

Synthetic Viral Pyrogen Induces Behavioral Fever in Plethodon Glutinosus Salamanders

Behavioral fever is an essential coping mechanism across ectothermic phyla to aid in combating pathogenic threats. Ectotherms lack internal temperature regulation associated with fever in endotherms; thus, ectotherms can exhibit a behavioral fever response when immunocompromised to thermoregulate by moving to warmer locations. The salamander order Caudata, tend to be keystone species in their resident ecosystems through their role as secondary consumers of invertebrates to maintain the food chain. With growing interest about ecology and conservation of salamanders as species diversity declines, this study was designed to determine if salamanders use their environment to take advantage of behavioral fever. The lungless salamander, Plethodon glutinosus, was used to investigate behavioral fever through exposure to the synthetic viral pyrogen polyinosinic:polycytidylic acid (Poly (I:C)) at doses of 15 µg/g by live wet weight. After 24 hours, the induced fever specimens were placed in a linear temperature gradient with a controlled humidity of 95% throughout. Average temperature preferences were then monitored over a 12-hour period and resulted in control animals preferring cold and moderate temperatures between 15-19 °C while all poly (I:C) injected animals preferred higher temperatures from 19-21°C (p\u3c\u3c0.0001). This result supports that P. glutinous responds to immunocompromising threats such as presented by synthetic viral pyrogen Poly (I:C) through use of behavioral fever

The Ancillary Benefits from Climate Policy in the United States

This study investigates the benefits to human health that would occur in the United States (U.S.) due to reductions in local air pollutant emissions stemming from a federal policy to reduce greenhouse gas emissions (GHG). In order to measure the impacts of reduced emissions of local pollutants, this study considers a representative U.S. climate policy. Specifically, the climate policy modeled in this analysis is the Warner-Lieberman bill (S.2191) of 2008 and the paper considers the impacts of reduced emissions in the transport and electric power sectors. This analysis provides strong evidence that climate change policy in the U.S. will generate significant returns to society in excess of the benefits due to climate stabilization. The total health-related co-benefits associated with a representative climate policy over the years 2006 to 2030 range between $90 and$725 billion in present value terms depending on modeling assumptions. The majority of avoided damages are due to reduced emissions of SO2 from coal-fired power plants. Among the most important assumptions is whether remaining coal-fired generation capacity is permitted to “backslide” up to the Clean Air Interstate Rule (CAIR) cap on emissions. This analysis models two scenarios specifically related to this issue. Co-benefits increase from $90 billion, when the CAIR cap is met, to$256 billion if SO2 emissions are not permitted to exceed current emission rates. On a per ton basis, the co-benefit per ton of GHG emissions is projected to average between $2 and$14 ($2006). The per ton marginal abatement cost for the representative climate policy is estimated at$9 ($2006).

Strategies to reduce the decline of wild bumble bees in North America: are they working?

Bumble bees are major pollinators of the world’s agricultural crops and wild plants and, as such, play a key role in maintaining economic prosperity and biodiversity. The decline of wild bumble bees in North America has been well-documented. However, the efficacy of strategies to prevent further decline have not been investigated thoroughly. This thesis involves a comprehensive literature review to examine the extent of, and reasons behind, the decline of wild bumble bee populations in North America and explore whether strategies implemented to prevent further decline are working. Results of this literature review revealed numerous stressors affecting bumble bee populations, but also indicated that reactions may differ between bumble bee species. The necessary species assessments are difficult to conduct because data pertaining to temporal and spatial occurrence are hard to obtain. Novel approaches to collecting bumble bee population data, such as the citizen science program Bumble Bee Watch, are important in augmenting the data collected by researchers. It is essential that existing databases be maintained to support ongoing monitoring. Long term conservation strategies must be established to preserve these important pollinators to ensure strong ecosystems have the necessary biodiversity to support the planet and its inhabitants. Essential areas of focus include habitat preservation and creation, bumble bee health and resource availability, use of pesticides, management of diseases and invasive species, building capacity through partnerships, education and training, research and effective monitoring programs. This information will be important in assessing the success of current mitigation strategies in the conservation and recovery of native bumble bees

Importance of site of infection and antibiotic selection in the treatment of carbapenem-resistant Pseudomonas aeruginosa sepsis

ABSTRACT In a retrospective analysis of 215 patients with carbapenem-resistant Pseudomonas aeruginosa sepsis, we observed a significantly higher risk of mortality associated with respiratory tract infection (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.04 to 1.39; P = 0.010) and lower risk with urinary tract infection (RR, 0.80; 95% CI, 0.71 to 0.90; P = 0.004). Aminoglycoside monotherapy was associated with increased mortality, even after adjusting for confounders (adjusted RR, 1.72; 95% CI, 1.03 to 2.85; P = 0.037), consistent across multiple sites of infection. </jats:p

Vancomycin 24-Hour Area under the Curve/Minimum Bactericidal Concentration Ratio as a Novel Predictor of Mortality in Methicillin-Resistant Staphylococcus aureus Bacteremia

While previous studies have examined the association between vancomycin (VAN) exposure and MIC with regard to outcomes in methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B), none have explored if a relationship exists with the VAN minimum bactericidal concentration (MBC). The objective of this study was to evaluate the VAN 24-h area under the curve (AUC24)/MBC ratio as a pharmacodynamic predictor of mortality. This retrospective cohort study included patients treated with VAN for MRSA-B with the primary outcome of 30-day all-cause mortality. Data collected included patient demographics, comorbidities, antimicrobial treatment data, therapeutic drug levels, and laboratory and microbiological data. Vancomycin MICs and MBCs were determined by Etest (MIC only) and broth microdilution (BMD). The vancomycin AUC24 was determined by pharmacokinetic maximum a posteriori probability Bayesian (MAP-Bayesian) analysis. The most significant breakpoint for 30-day mortality was determined by classification and regression tree (CART) analysis. The association between pharmacodynamic parameters (VAN AUC24/MICBMD, VAN AUC24/MICEtest, and AUC24/MBCBMD) and mortality were determined by χ2 and multivariable Poisson regression. Overall mortality in this cohort (n = 53) was 20.8% (n = 11/53), and all corresponding MRSA blood isolates were VAN susceptible (MIC range, 0.5 to 2 μg/ml; MIC50, 1 μg/ml; MIC90, 1 μg/ml). The CART-derived breakpoints for mortality were 176 (VAN AUC24/MBC) and 334 (VAN AUC24/MICBMD). In multivariable analysis, the association between a VAN AUC24/MBC of ≥176 and survival persisted, but VAN AUC24/MICBMD values (≥334 or ≥400) were not associated with improved mortality. In conclusion, VAN AUC24/MBC was a more important predictor of 30-day mortality than VAN AUC24/MIC for MRSA-B

Extracellular vesicles: Novel communicators in lung diseases

This work is licensed under a Creative Commons Attribution 4.0 International License.The lung is the organ with the highest vascular density in the human body. It is therefore perceivable that the endothelium of the lung contributes significantly to the circulation of extracellular vesicles (EVs), which include exosomes, microvesicles, and apoptotic bodies. In addition to the endothelium, EVs may arise from alveolar macrophages, fibroblasts and epithelial cells. Because EVs harbor cargo molecules, such as miRNA, mRNA, and proteins, these intercellular communicators provide important insight into the health and disease condition of donor cells and may serve as useful biomarkers of lung disease processes. This comprehensive review focuses on what is currently known about the role of EVs as markers and mediators of lung pathologies including COPD, pulmonary hypertension, asthma, lung cancer and ALI/ARDS. We also explore the role EVs can potentially serve as therapeutics for these lung diseases when released from healthy progenitor cells, such as mesenchymal stem cells.NiH R01DA042715NIH R01HL129875NIH P20 GM10363

The Effects of Pregnenolone 16α-Carbonitrile Dosing on Digoxin Pharmacokinetics and Intestinal Absorption in the Rat

The effect of Pgp induction in rats by pregnenolone 16α-carbonitrile (PCN) (3 days, 35 mg/kg/d, p.o.) on digoxin pharmacokinetics and intestinal transport has been assessed. After intravenous or oral digoxin dosing the arterial and hepatic portal vein (oral) AUC(0-24h) were significantly reduced by PCN pre-treatment. Biliary digoxin clearance increased 2-fold following PCN treatment. PCN significantly increased net digoxin secretion (2.05- and 4.5-fold respectively) in ileum and colon but not in duodenum or jejunum. This increased secretion correlated with increased Pgp protein expression in ileum and colon. Both intestinal and biliary excretion therefore contribute to altered digoxin disposition following PCN

IMMUNODEFICIENT R2G2 MOUSE STRAIN YIELDS SPLEENS WITH UNUSUAL CYTOARCHITECTURE AND SYMPATHETIC INNERVATION

The nervous system and immune system contact one another through two-way communication in order to establish and preserve homeostasis. The sympathetic neurotransmitter norepinephrine has an impact on how the immune system responds by affecting regional blood flow and activation of adrenergic receptors on leukocytes. Former studies showed that immune cells are capable of releasing nerve growth factor allowing for the establishment and continuation of sympathetic nerves in targeted tissues. From this gathered information, it was hypothesized that sympathetic nerves would prove to be less frequent in spleens from the immunodeficient R2G2 mouse strain (Envigo) when compared to 129P3/J (129) and C57BL/6 (C57) strains. R2G2 mice are an immunodeficient strain that lacks functional T, B, and natural killer cells. Ten to eleven week aged-matched male mice were measured by body weight, spleen weight, and temperature. Spleens were cut and fixed for histological investigation. Sympathetic nerves were labeled by immunostaining tyrosine hydroxylase (TH). Hematoxylin & eosin (H&E) was used to stain spleen sections in order to evaluate cytoarchitecture. Von Willebrand factor (VWF) was used to immunostain for megakaryocytes. R2G2 mice showed slightly higher temperatures and body weights but yielded a significantly smaller spleen weight (R2G2, 38.20 ± 1.48; 129, 65.08 ± 11.71; C57, 81.33 ± 8.38; P\u3c 0.0001, ANOVA). TH stain revealed sympathetic innervation in all strains but location and morphology differed in R2G2 mice compared to controls. Control spleens had nerves which entered white pulp regions of the spleen and were closely related to leukocytes. Fiber profiles in the controls were filamentous with small acute bends. R2G2 differed by having (TH+) nerve fibers more associated with arteries and less localized in the surrounding parenchyma. The fibers were abnormally swollen and held a more granular shape instead of a filamentous shape. The H&E stain showed clear red and white pulp zones in the control spleens with 129 showing more distinct germinal centers than C57. R2G2 H&E sections showed cytoarchitecture with indistinct pulp areas. VWF staining revealed R2G2 mice had an abundant amount of megakaryocytes versus control mice megakaryocyte counts (R2G2, 11.28 ± 3.87 per 20X field; 129, 1.73 ± 0.70; C57, 1.42 ± 0.13; P\u3c 0.0001, ANOVA) and extramedullary hematopoiesis was highly prominent. This evidence supports that leukocytes secrete neurotrophic factors or are vital to establishing normal growth of TH+ nerves toward the white pulp. Leukocytes may not be required for sympathetic innervation of blood vessels in the spleen, however, lack of leukocytes shows TH+ nerve fibers with abnormal morphology in severely immune threatened mice