Background Invasive mold infections (IMI) directly impact life expectancy, especially with delayed therapy. Among IMI, aspergillosis (IA) is more common than mucormycosis (IM), resulting in IA-targeted empirical treatment with voriconazole for suspected invasive pulmonary aspergillosis (IPA), despite IM ineffectiveness. Recently, isavuconazole was approved in Canada for IA and IM. The primary objective was to assess the cost-effectiveness of isavuconazole compared to voriconazole for suspected IPA in Canada. A secondary objective was to assess the impact of varying time horizons to address the wide spectrum of life expectancies, according to patients underlying diseases. Research Design and Methods A 5-year decision-tree was developed from the Canadian Ministry of Health (MoH) and societal perspectives. Efficacy parameters were extracted from SECURE/VITAL trials. Costs included treatment acquisition, hospitalization, adverse events and productivity loss. 3- and 10-year time horizon alternative scenarios and extensive sensitivity analyses were also conducted. Results From a MoH perspective, isavuconazole compared to voriconazole resulted in an incremental cost-utility ratio (ICUR) of $C30,160/QALY. 3- and10-year ICURs were also cost-effective, relative to a willingness-to-pay threshold of $C50,000/QALY. Conclusions This study demonstrates that, in comparison to voriconazole, isavuconazole is a cost-effective strategy for the treatment of patients with suspected IPA, regardless of their life expectancy.

Budesonide orodispersible tablets (BOT) have been approved in Europe and Canada for the treatment of eosinophilic esophagitis (EoE), a rare and chronic disease. The objective of this study was to assess the economic impact of BOT on both the induction and maintenance of clinico-pathological remission of EoE by performing a cost–utility analysis (CUA). For both the induction and maintenance settings, BOT was compared to no treatment in a target population of adult patients with EoE non-responsive to proton pump inhibitor (PPI) treatment. Markov models were developed for the induction and maintenance settings over 52-week and life-time horizons, respectively. Analyses were performed from both a Canadian Ministry of Health (MoH) and societal perspective. The resulting incremental cost–utility ratios (ICURs) were compared to a willingness-to-pay (WTP) threshold of $50,000 Canadian dollars/quality-adjusted life-year (QALY). Sensitivity and scenario analyses were conducted to assess the robustness of the base-case results. In the base-case probabilistic analysis, BOT compared to no treatment resulted in an ICUR of $1073/QALY and $30,555/QALY from a MoH perspective in the induction and maintenance settings, respectively. BOT was a cost-effective option for both induction and maintenance in > 99% of Monte Carlo simulations. In the scenario analyses, the deterministic ICUR of BOT compared to no treatment varied from $682/QALY to $8510/QALY in the induction setting and $21,005/QALY to $55,157/QALY in the maintenance setting. BOT was cost-effective compared to no treatment for both the induction and maintenance of clinico-pathological remission of EoE in patients non-responsive to PPIs.

Invasive mold infections (IMI) are associated with considerable morbidity and mortality in immunocompromised hosts, with fatality rates approaching 100% when therapy is delayed. Among IMI, aspergillosis (IA) is far more common than mucormycosis (IM). As a result, IA-targeted empirical treatment with voriconazole is often initiated in patients with suspected pulmonary IMI, but this therapy overlooks IM. Recently, isavuconazole has been approved in Canada as a monotherapy for the treatment of both IA and IM. The objective of this study was to assess the economic impact of isavuconazole compared to voriconazole for the treatment of suspected pulmonary IMI in Canada. A decision tree was developed over a 5-year time horizon from the Canadian Ministry of Health (MoH) and societal perspectives. The target population were patients with suspected pulmonary IMI, among which IA and IM were estimated to account for 95% and 5%, respectively. Efficacy parameters, including the percentage of patients using a second-line treatment and the rate of all-cause mortality, were extracted from the isavuconazole trials (SECURE and VITAL). Costs included were those associated with treatment acquisition, hospitalization, management of adverse events and productivity loss. Deterministic and probabilistic sensitivity analyses (PSA) were also conducted. Isavuconazole was associated with a gain of 0.146 QALY, compared to voriconazole for IMI. From a MoH perspective, isavuconazole and voriconazole were associated with total costs of $C48,479 and $C44,088, respectively (difference $C4,391), which resulted in an incremental cost-utility ratio of $C30,160/QALY. were similar from a societal perspective. PSA for isavuconazole showed that it remained a cost-effective strategy in 62% of simulations from a MoH perspective, relative to a willingness to pay threshold of $C50,000/QALY. This economic evaluation demonstrates that, in comparison to voriconazole, isavuconazole is a cost-effective strategy for the treatment of patients suspected of having an IMI.

Abstract Topical corticosteroids are the foundation of pharmacologic treatment for eosinophilic oesophagitis (EoE) and administered mainly as nebulized swallowed fluticasone or budesonide viscous solution (BVS). Recently, a budesonide orodispersible tablet (BOT) has been approved for the treatment of EoE. The ideal formulation of topical corticosteroid delivery is unclear. Therefore, we aimed to compare the efficacy of BOT with other topical corticosteroid formulations for achieving histological remission in adult patients with EoE in a network meta-analysis (NMA). Methods A systematic literature review was performed using Medline and EMBASE from 1990 to July 2019. Eligible studies evaluated adult patients with a diagnosis of EoE treated with a topical corticosteroid in a randomized controlled trial. The outcome of interest was the proportion of patients achieving induction of histological remission (peak esophageal eosinophil count <5 eosinophils/high-power field). Direct comparisons were performed using the Mantel–Haenszel method and an NMA was performed using a fixed effect Bayesian framework with Markov Chain Monte Carlo simulations. Heterogeneity between studies was analyzed using the Cochrane Q test and consistency was verified. Results The search yielded 321 references and 6 (447 patients) were included in the quantitative summary. In the NMA, all formulations of topical corticosteroids were associated with greater histological remission rates than placebo. BOT was associated with a significantly higher rate of histological remission compared to BVS (odds ratio [OR] = 4.9; 95% credible interval [CrI] = 1.4,19.1), fluticasone (OR = 7.4; 95%CrI = 1.7,34.5), nebulized swallowed budesonide (NSB) (OR = 25.0; 95%CrI = 2.9,247.2) and placebo (OR = 387.6; 95%CrI = 97.5,2275.6). Similar trends were shown in direct comparisons. Analysis of the ranking of treatment options based on probability of effectiveness found BOT to be most probable followed by BVS, fluticasone, NSB, and placebo, consecutively. Conclusion This NMA of randomized controlled trials suggests that BOT is significantly more likely to achieve histological remission in adult patients with EoE compared to BVS, fluticasone, and NSB. We hypothesize that the superiority of BOT is related to increased contact time and targeting all inflammatory sites in the oesophagus, in contrast to other formulations. This NMA suggest that BOT is the first choice therapy amongst topical corticosteroids for the management of EoE.

Topical corticosteroids, comprised mainly of fluticasone multi-dose inhaler content swallowed or budesonide viscous solution (BVS), are the foundation of treatment for eosinophilic oesophagitis (EoE). Recently, a budesonide orodispersible tablet (BOT) has been approved for the treatment of EoE. Given the absence of direct comparisons, we evaluated the relative efficacy of BOT with other topical corticosteroid formulations for inducing histological remission in patients with EoE by a network meta-analysis (NMA). A systematic literature review was performed using MEDLINE and Embase up to August 1, 2019. Eligible studies comprised randomised controlled trials (RCTs) which evaluated adult patients with a diagnosis of active EoE treated with a topical corticosteroid in comparison to placebo or another topical corticosteroid. The outcome of interest was the proportion of patients achieving induction of histological remission defined as a peak oesophageal eosinophil count of <5 eosinophils/high-power field. Direct comparisons were made using the Mantel-Haenszel method and an NMA was performed using a fixed effects Bayesian framework with Markov Chain Monte Carlo simulations. A total of 6 trials (n=447 patients) were included in the quantitative summary. The NMA determined that BOT was associated with a higher odds of histological remission compared to BVS (odds ratio [OR]=4.9 [95% credible interval [CrI]=1.4, 19.1]), fluticasone (7.4 [1.7, 34.5]), nebulised swallowed budesonide (NSB) (25.0 [2.9, 247.2]) and placebo (387.6 [97.5, 2,275.6]). Similar findings were observed for direct comparisons. This NMA of RCTs suggest that BOT is significantly more likely to achieve histological remission in adult patients with EoE compared to BVS, fluticasone, and NSB.

ACTERO Listeria Enrichment Media (ACTERO Listeria) is a selective medium developed for a single-step recovery and enrichment of Listeria spp. from environmental samples. Robustness testing of the ACTERO Listeria medium demonstrated good performance when minor changes were introduced to the incubation temperature and time. All 54 Listeria strains tested, representing the most frequently isolated Listeria species from food (L. monocytogenes, L. ivanovii, L. seeligeri, L. welshimeri, and L. grayi), were successfully enriched in ACTERO Listeria. None of the 30 nontarget strains tested in the exclusivity study was recovered after incubation in ACTERO Listeria. Recovery of Listeria was consistent across three independently produced lots of the ACTERO Listeria, and the prepared medium was stable for 45 days when stored at 4 degrees C in the dark. Matrix studies performed with environmental sponge samples from plastic and stainless steel surfaces demonstrated similar recovery of Listeria spp. in a single-step enrichment using ACTERO Listeria from plastic, and significantly better recovery from stainless steel surfaces when compared to the U.S. Department of Agriculture-Food Safety and Inspection Service reference method. The results of this study prove that ACTERO Listeria Enrichment Media can be effectively used in replacement of the two-step enrichment suggested by the reference method without affecting the recovery of Listeria spp. from environmental samples.

Published Ahead of Print 18 June 2012. 10.1128/AAC.00726-12. 2012, 56(9):4662. DOI: Antimicrob. Agents Chemother. Lynn Miesel Katherine Young, Simon Wong, Sherman T. Waddell and Powles, Kathryn I. Skorey, John Tam, Christopher M. Tan, Benton-Perdomo, Mihai Petcu, John W. Phillips, Mary Ann Painter, Craig A. Parish, Young-Whan Park, Liliana Molly M. Lin, Anna A. Michels, Aimie M. Ogawa, Ronald E. Penny S. Leavitt, Christian Lebeau-Jacob, Suzy S. Lee, Michel Gallant, Xin Gu, Nancy J. Kevin, Josiane Lafleur, Deschamps, Robert G. K. Donald, Andrew M. Galgoci, Beaulieu, Alexandre Caron, David Claveau, Kathleen Alex G. Therien, Joann L. Huber, Kenneth E. Wilson, Patrick Peptidase Type I Antibiotics through Inhibition of Signal -Lactam β Broadening the Spectrum of

Despite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to β-lactam antibiotics paired with β-lactamase inhibitors. We have adapted a Staphylococcus aureus antisense knockdown strategy to genetically identify the cell division Z ring components-FtsA, FtsZ, and FtsW-as β-lactam susceptibility determinants of methicillin-resistant S. aureus (MRSA). We demonstrate that the FtsZ-specific inhibitor PC190723 acts synergistically with β-lactam antibiotics in vitro and in vivo and that this combination is efficacious in a murine model of MRSA infection. Fluorescence microscopy localization studies reveal that synergy between these agents is likely to be elicited by the concomitant delocalization of their cognate drug targets (FtsZ and PBP2) in MRSA treated with PC190723. A 2.0 Å crystal structure of S. aureus FtsZ in complex with PC190723 identifies the compound binding site, which corresponds to the predominant location of mutations conferring resistance to PC190723 (PC190723(R)). Although structural studies suggested that these drug resistance mutations may be difficult to combat through chemical modification of PC190723, combining PC190723 with the β-lactam antibiotic imipenem markedly reduced the spontaneous frequency of PC190723(R) mutants. Multiple MRSA PC190723(R) FtsZ mutants also displayed attenuated virulence and restored susceptibility to β-lactam antibiotics in vitro and in a mouse model of imipenem efficacy. Collectively, these data support a target-based approach to rationally develop synergistic combination agents that mitigate drug resistance and effectively treat MRSA infections.

BACKGROUND:Oxidative Stress contributes to the pathogenesis of many diseases. The NRF2/KEAP1 axis is a key transcriptional regulator of the anti-oxidant response in cells. Nrf2 knockout mice have implicated this pathway in regulating inflammatory airway diseases such as asthma and COPD. To better understand the role the NRF2 pathway has on respiratory disease we have taken a novel approach to define NRF2 dependent gene expression in a relevant lung system.METHODS:Normal human lung fibroblasts were transfected with siRNA specific for NRF2 or KEAP1. Gene expression changes were measured at 30 and 48 hours using a custom Affymetrix Gene array. Changes in Eotaxin-1 gene expression and protein secretion were further measured under various inflammatory conditions with siRNAs and pharmacological tools.RESULTS:An anti-correlated gene set (inversely regulated by NRF2 and KEAP1 RNAi) that reflects specific NRF2 regulated genes was identified. Gene annotations show that NRF2-mediated oxidative stress response is the most significantly regulated pathway, followed by heme metabolism, metabolism of xenobiotics by Cytochrome P450 and O-glycan biosynthesis. Unexpectedly the key eosinophil chemokine Eotaxin-1/CCL11 was found to be up-regulated when NRF2 was inhibited and down-regulated when KEAP1 was inhibited. This transcriptional regulation leads to modulation of Eotaxin-1 secretion from human lung fibroblasts under basal and inflammatory conditions, and is specific to Eotaxin-1 as NRF2 or KEAP1 knockdown had no effect on the secretion of a set of other chemokines and cytokines. Furthermore, the known NRF2 small molecule activators CDDO and Sulphoraphane can also dose dependently inhibit Eotaxin-1 release from human lung fibroblasts.CONCLUSIONS:These data uncover a previously unknown role for NRF2 in regulating Eotaxin-1 expression and further the mechanistic understanding of this pathway in modulating inflammatory lung disease.

ABSTRACT The resistance of methicillin-resistant Staphylococcus aureus (MRSA) to all β-lactam classes limits treatment options for serious infections involving this organism. Our goal is to discover new agents that restore the activity of β-lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin), which potentiate the activity of imipenem against MRSA strain COL. We report here that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems. A synthetic derivative of actinocarbasin, M131, synergized with imipenem both in vitro and in vivo with potent efficacy. The in vitro activity of M131 extends to clinical isolates of MRSA but not to a methicillin-sensitive strain. Synergy is restricted to β-lactam antibiotics and is not observed with other antibiotic classes. We propose that the SpsB inhibitors synergize with β-lactams by preventing the signal peptidase-mediated secretion of proteins required for β-lactam resistance. Combinations of SpsB inhibitors and β-lactams may expand the utility of these widely prescribed antibiotics to treat MRSA infections, analogous to β-lactamase inhibitors which restored the utility of this antibiotic class for the treatment of resistant Gram-negative infections.

Connecting bacterial growth inhibitors to molecular targets at the whole-cell level is a major impediment to antibacterial development. Herein we report the design of a highly efficient and versatile bacteriophage-based mariner transposon delivery system in Staphylococcus aureus for determining inhibitor mode of action. Using bacteriophage-mediated delivery of concatameric minitransposon cassettes, we generated nonclonal transposant libraries with genome-wide insertion-site coverage in either laboratory or methicillin-resistant strain backgrounds and screened for drug resistance in situ on a single agar plate in one step. A gradient of gene-target expression levels, along with a correspondingly diverse assortment of drug-resistant phenotypes, was achieved by fitting the transposon cassette with a suite of outward-facing promoters. Using a panel of antibiotics, we demonstrate the ability to unveil not only an inhibitor's molecular target but also its route of cellular entry, efflux susceptibility and other off-target resistance mechanisms.

A novel series of trisubstituted ureas has been identified as potent and selective mPGES-1 inhibitors. These compounds are selective over other prostanoid enzymes such as PGF synthase and TX synthase. This series of inhibitors was developed by lead optimization of a hit from an internal HTS campaign. Lead compound 42 is potent in A549 cell assay (IC(50) of 0.34 μM) and in human whole blood assay (IC(50) of 2.1 μM). An efficient and versatile one-pot strategy for the formation of ureas, involving a reductive amination, was developed to generate these inhibitors.

The antibacterial activities of nano-crystalline metallic oxides (CaO, MgO and ZnO), prepared by sonication-thermal decomposition method, and micrometric metal oxides were evaluated on three strains of lactic bacteria, Lactobacillus plantarum, Lactobacillus helviticus and Leuconostoc mesenteroides, and on spores of Alicyclobacillus acidoterresris involved in fruit juice spoilage. The effects of particle size, pH, concentration and exposure time on the viability were examined in physiological solution as well as culture broth. The tests were performed by adding the bacterial or spore suspensions in flasks containing metal oxides. The results showed that CaO nanoparticle was the most effective in killing all the three strains of lactic bacteria exposed for 24 h at 100 ppm, but its antibacterial activity is attributable in part to its pH effect. MgO was lethal against L. helveticus, but exhibited little effect against either L. mesenteroides or L. plantarum. The nanoparticular ZnO clearly showed a bactericidal effect on all lactic bacteria tested, but less so against L. helveticus, and it was also more effective in inhibiting their growth compared with alkaline metal oxides. No antibacterial effect of the metal oxides was observed against the spores of A. acidoterrestris. This investigation showed that, in general, higher concentration, longer exposure and smaller particles size of metal oxides tend to increase their antibacterial effect. However, the aggregation of nanoparticles at high concentrations of metal oxides in the slurry tends to lower the antimicrobial action. It was also evident that the antibacterial activity of metal oxides depends on the type of metal oxide (alkaline or amphoteric) and on the morphological and physiological characteristics of the bacteria.

Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.

The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC50 < 10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC50 < 0.5 mu M) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis. (c) 2008 Elsevier Ltd. All rights reserved.

A biologically inspired approach to active visual target tracking is presented. The approach makes use of three strategies found in biological systems: space-variant sensing, a spatio-temporal-frequency-based model of motion detection and the alignment of sensory-motor maps. Space-variant imaging is used to create a 1D array of elementary motion detectors (EMDs) that are tuned in such a way as to make it possible to detect motion over a wide range of velocities while still being able to detect motion precisely. The array is incorporated into an active visual tracking system. A method of analysis and design for such a tracking system is proposed. It makes use of a sensory-motor map which consists of a phase-plane plot of the continuous-time dynamics of the tracking system overlaid onto a map of the detection capabilities of the array of EMDs. This sensory-motor map is used to design a simple 1D tracking system and several simulations show how the method can be used to control tracking performance using such metrics as overshoot and settling time. A complete 1D active vision system is implemented and a set of simple target tracking experiments are performed to demonstrate the effectiveness of the approach.

Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 microM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development.

CaO is an important inorganic material, which can be used as catalyst, toxic-waste remediation agent, adsorbent etc. in order to make use of CaO, nano-CaO was prepared by thermal-decomposition method using Ca(NO(3))(2).4H(2)O as precursor, NaOH aqueous solution as precipitant, and ethylene glycol as medium in this paper. Characteristics of samples were measured by TGA, XRD, TEM et al techniques. The results showed that the size of nano-CaO about 14 nm could be obtained under the conditions (calcinations temperature 500 degrees C, calcinations time 1.5 h, heating rate of calcinations 5 degrees C/min). It is a very simple and effective method to prepare nano-CaO. (C) 2007 Elsevier B.V All rights reserved.