Comparative Effectiveness of Linezolid and Vancomycin Among a National Veterans Affairs Cohort with Methicillin-Resistant Staphylococcus aureus Pneumonia

Study Objective: As variability in vancomycin dosing, susceptibility, and tolerability has driven the need to compare newer agents with vancomycin in real-world clinical settings, we sought to quantify the effectiveness of linezolid compared with vancomycin on clinical outcomes for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Design: Retrospective cohort study. Data Source: Veterans Health Administration national databases. Patients: Adults admitted to Veterans Affairs hospitals between January 2002 and September 2010 with diagnosis codes for MRSA and pneumonia, and who initiated and received at least 3 days of continuous intravenous vancomycin therapy (4943 patients) or intravenous or oral linezolid therapy (328 patients) while in the hospital. Measurements and Main Results: Propensity score–adjusted Cox proportional hazards regression models quantified the effect of linezolid compared with vancomycin on time to 30-day mortality (primary outcome), therapy change, hospital discharge, discharge from intensive care, intubation, 30-day readmission, and 30-day MRSA reinfection. In addition, a composite outcome of clinical success was defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation by day 14. Subgroup analyses were performed in a validated microbiology-confirmed MRSA subgroup and clinical subgroup meeting clinical criteria for infection. Although a number of baseline variables differed significantly between the vancomycin and linezolid treatment groups, balance was achieved within propensity score quintiles. A significantly lower rate of therapy change was observed in the linezolid group (adjusted hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.48–0.96). The clinical success rate was significantly higher among patients treated with linezolid (adjusted HR 1.25, 95% CI 1.07–1.47). Comparable findings were observed in the subgroup analyses. Conclusion: Individual clinical outcomes were similar among patients treated for MRSA pneumonia with linezolid compared with vancomycin. A significantly higher rate of the composite outcome of clinical success was observed, however, among patients treated with linezolid compared with vancomycin

Predictors of Clinical Success Among a National Veterans Affairs Cohort With Methicillin-Resistant Staphylococcus aureus Pneumonia

Background: The treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is exceedingly complicated, which is concerning because of the high mortality rate associated with the infection. Identification of independent predictors of clinical success can optimize patient care by assisting clinicians in treatment decisions. Objectives: We sought to identify independent predictors of clinical success in a national Veterans Affairs (VA) cohort of MRSA pneumonia patients. Methods: A nested case-control study was conducted among a cohort of VA patients with MRSA pneumonia receiving linezolid or vancomycin between January 2002 and September 2010. Cases included those demonstrating clinical success, defined as discharge from the hospital or intensive care unit (ICU) by day 14 after treatment initiation, in the absence of death, therapy change, or intubation by day 14. Controls represented non-success, defined as therapy change, intubation, ICU admission, re-admission, or death between treatment initiation and day 14. The potential predictors assessed included treatment, patient demographics and admission characteristics, previous healthcare and medication exposures, comorbidities, and medical history. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from logistic regression. Results: Our study included 2442 cases of clinical success and 1290 controls. Demographics varied between the clinical success and non-success groups, including age, race, and region of facility. A current diagnosis of chronic respiratory disease (46% vs 42%) and diagnosis of pneumonia in the year prior to the MRSA pneumonia admission (37% vs 32%) were both more common in the clinical success group. Despite these significant differences, only two predictors of clinical success were identified in our study: previous complication of an implant or graft, including mechanical complications and infections, in the year prior to the MRSA pneumonia admission (OR, 1.55; 95% CI, 1.17–2.06) and treatment with linezolid (1.53; 1.12–2.10). Predictors of non-success included concomitant urinary tract infection diagnosis (OR, 0.82; 95% CI, 0.70–0.96), intravenous line (0.76; 0.66–0.89), previous coagulopathy (0.74; 0.56–0.96), previous amputation procedure (0.72; 0.53–0.98), current coagulopathy diagnosis (0.71; 0.53–0.96), dialysis (0.54; 0.38–0.76), multiple inpatient procedures (0.53; 0.45–0.62), inpatient surgery (0.48; 0.41–0.57), and previous endocarditis (0.24; 0.07–0.81). Discussion: MRSA pneumonia tends to affect complex patients, and identification of the predictors of clinical success is useful when considering different therapeutic approaches. Conclusions: In a national cohort of VA patients with MRSA pneumonia, treatment was the only modifiable variable predicting clinical success

The Comparative Effectiveness of Ceftolozane/Tazobactam versus Aminoglycoside- or Polymyxin-Based Regimens in Multi-Drug-Resistant Pseudomonas aeruginosa Infections

Pseudomonas aeruginosa infections are challenging to treat due to multi-drug resistance (MDR) and the complexity of the patients affected by these serious infections. As new antibiotic therapies come on the market, limited data exist about the effectiveness of such treatments in clinical practice. In this comparative effectiveness study of ceftolozane/tazobactam versus aminoglycoside- or polymyxin-based therapies among hospitalized patients with positive MDR P. aeruginosa cultures, we identified 57 patients treated with ceftolozane/tazobactam compared with 155 patients treated with aminoglycoside- or polymyxin-based regimens. Patients treated with ceftolozane/tazobactam were younger (mean age 67.5 vs. 71.1, p = 0.03) and had a higher comorbidity burden prior to hospitalization (median Charlson 5 vs. 3, p = 0.01) as well as higher rates of spinal cord injury (38.6% vs. 21.9%, p = 0.02) and P. aeruginosa-positive bone/joint cultures (12.3% vs. 0.7%, p \u3c 0.0001). Inpatient mortality was significantly lower in the ceftolozane/tazobactam group compared with aminoglycosides or polymyxins (15.8% vs. 27.7%, adjusted odds ratio 0.39, 95% confidence interval 0.16–0.93). There were no significant differences observed for the other outcomes assessed. In hospitalized patients with MDR P. aeruginosa, inpatient mortality was 61% lower among patients treated with ceftolozane/tazobactam compared to those treated with aminoglycoside- or polymyxin-based regimens

Biomass and Productivity of Thalassia testudinum in Estuaries of the Florida Panhandle

Thalassia testudinum often dominates seagrass meadows of the Florida panhandle but few measurements of productivity, biomass, density, turnover or leaf area index in this region have been made. We targeted 5 estuaries located at similar latitudes, 30⁰ ± 0.3⁰N: Big Lagoon, Santa Rosa Sound, St. Andrew Bay, St. Joseph Bay, and St. George Sound. This study was one component of a collaborative partnership of state and local researchers examining factors preventing recovery in panhandle estuarine areas that had historically contained seagrass in the 1940s and 1950s. Measurements were made twice in 2016, once in June and then again in summer or fall, except in Santa Rosa Sound where measurements were made 3 times. In the estuaries sampled for the second time in July or August, aboveground productivity was greater than in June. St. Joseph Bay had the highest aboveground productivity (4.3 g/m2/d) and 1—sided leaf area index (4.2) while St. George Sound had the lowest values (0.41 g/m2/d and 1.0). Principal component analysis suggested that St. Andrew Bay, Big Lagoon and Santa Rosa Sound were the most similar, with higher values for shoot densities and leaf turnover and lower salinities and watershed:water ratios. St. Joseph Bay had high aboveground productivity and salinity, and low turbidity. St. George Sound had low aboveground productivity, high total suspended solids and the highest watershed:water ratio. These baseline productivity estimates will be useful to assess the success of restoration efforts targeting seagrasses in the Florida panhandle and evaluate impacts of climate change on seagrasses

3D-imaging of Printed Nanostructured Networks using High-resolution FIB-SEM Nanotomography

Networks of solution-processed nanomaterials are important for multiple applications in electronics, sensing and energy storage/generation. While it is known that network morphology plays a dominant role in determining the physical properties of printed networks, it remains difficult to quantify network structure. Here, we utilise FIB-SEM nanotomography to characterise the morphology of nanostructured networks. Nanometer-resolution 3D-images were obtained from printed networks of graphene nanosheets of various sizes, as well as networks of WS2 nanosheets, silver nanosheets and silver nanowires. Important morphological characteristics, including network porosity, tortuosity, pore dimensions and nanosheet orientation were extracted and linked to network resistivity. By extending this technique to interrogate the structure and interfaces within vertical printed heterostacks, we demonstrate the potential of this technique for device characterisation and optimisation.Comment: 6 figure

Phosphomannose isomerase and phosphomannomutase gene disruptions in Streptomyces nodosus: impact on amphotericin biosynthesis and implications for glycosylation engineering

Streptomycetes synthesise several bioactive natural products that are modified with sugar residues derived from GDP-mannose. These include the antifungal polyenes, the antibacterial antibiotics hygromycin A and mannopeptimycins, and the anticancer agent bleomycin. Three enzymes function in biosynthesis of GDP-mannose from the glycolytic intermediate fructose 6-phosphate: phosphomannose isomerase (PMI), phosphomannomutase (PMM) and GDP-mannose pyrophosphorylase (GMPP). Synthesis of GDP-mannose from exogenous mannose requires hexokinase or phosphotransferase enzymes together with PMM and GMPP. In this study, a region containing genes for PMI, PMM and GMPP was cloned from Streptomyces nodosus, producer of the polyenes amphotericins A and B. Inactivation of the manA gene for PMI resulted in production of amphotericins and their aglycones, 8-deoxyamphoteronolides. A double mutant lacking the PMI and PMM genes produced 8-deoxyamphoteronolides in good yields along with trace levels of glycosylated amphotericins. With further genetic engineering these mutants may activate alternative hexoses as GDP-sugars for transfer to aglycones in vivo.Higher Education AuthorityUniversity College Dubli

West Nile Virus and Wildlife

West Nile virus (WNV) has spread rapidly across North America, resulting in human deaths and in the deaths of untold numbers of birds, mammals, and reptiles. The virus has reached Central America and the Caribbean and may spread to Hawaii and South America. Although tens of thousands of birds have died, and studies of some bird species show local declines, few region-wide declines can be attributed to WNV. Predicting future impacts of WNV on wildlife, and pinpointing what drives epidemics, will require substantial additional research into host susceptibility, reservoir competency, and linkages between climate, mosquitoes, and disease. Such work will entail a collaborative effort between scientists in governmental research groups, in surveillance and control programs, and in nongovernmental organizations. West Nile virus was not the first, and it will not be the last, exotic disease to be introduced to the New World. Its spread in North America highlights the need to strengthen animal monitoring programs and to integrate them with research on disease ecology

Development and optimization of a high-throughput screening method utilizing Ancylostoma ceylanicum egg hatching to identify novel anthelmintics.

Hookworms remain a major health burden in the developing world, with hundreds of millions currently afflicted by these blood-feeding parasites. There exists a vital need for the discovery of novel drugs and identification of parasite drug targets for the development of chemotherapies. New drug development requires the identification of compounds that target molecules essential to parasite survival and preclinical testing in robust, standardized animal models of human disease. This process can prove costly and time consuming using conventional, low-throughput methods. We have developed a novel high-throughput screen (HTS) to identify anthelmintics for the treatment of soil-transmitted helminths. Our high-throughput, plate reader-based assay was used to rapidly assess compound toxicity to Ancylostoma ceylanicum L1 larva. Using this method, we screened 39,568 compounds from several small molecule screening libraries at 10 μM and identified 830 bioactive compounds that inhibit egg hatching of the human hookworm A. ceylanicum by >50%. Of these, 132 compounds inhibited hookworm egg hatching by >90% compared to controls. The nematicidal activities of 268 compounds were verified by retesting in the egg hatching assay and were also tested for toxicity against the human HeLa cell line at 10 μM. Fifty-nine compounds were verified to inhibit A. ceylanicum egg hatching by >80% and were <20% toxic to HeLa cells. Half-maximal inhibitory concentration (IC50) values were determined for the 59 hit compounds and ranged from 0.05-8.94 μM. This stringent advancement of compounds was designed to 1) systematically assess the nematicidal activity of novel compounds against the egg stage of A. ceylanicum hookworms in culture and 2) define their chemotherapeutic potential in vivo by evaluating their toxicity to human cells. Information gained from these experiments may directly contribute to the development of new drugs for the treatment of human hookworm disease