High throughput screening of small molecule libraries for modifiers of radiation responses

Purpose:?An unbiased approach of drug discovery through high-throughput screening (HTS) of libraries of chemically defined and bioactive small molecule compounds was used to identify modulators of radiation injury with an emphasis on radioprotectors and mitigators rather than radiosensitisers. Assay system endpoints included radiation-induced genotoxicity and DNA damage in yeast and apoptosis in murine lymphocytes. Large-scale data mining of chemically diverse libraries identified agents that were effective with all endpoints. HTS of bioactive compound libraries against murine lymphocytes profiled tetracycline and fluoroquinolone antibiotics and cyclopiazonic acid as having activity, and structure-activity analysis showed a common pharmacophore. Purine nucleosides, the interferon inducer tilorone, and linoleic acid were also identified as potential mitigators of radiation damage that often were also radioprotective. Many of these compounds enhance DNA repair, have anti-inflammatory activity, and stimulate hematopoiesis. Selected compounds within these initial verified hits from both types of libraries identified potent mitigators of lethal whole body irradiation (WBI) in mice.

Conclusion:?In spite of the fact that in vitro HTS has limitations and is unable to fully recapitulate all aspects of the complex in vivo acute radiation response, it identified several classes of molecules that had activity as radioprotectors and radiomitigators of the hematopoietic system in vivo. In the future, addition of 3-dimensional (3-D) or stem cell cultures or pathway analysis, may improve the power of HTS, but our findings indicate that common, evolutionary conserved, canonical pathways can be identified that could be exploited to mitigate radiation-induced defects.     

Current recommendations for Helicobacter pylori therapies in a world of evolving resistance

Occurrence of resistance, especially to clarithromycin, renders the standard triple therapy used to cure Helicobacter pylori infection ineffective. This review presents the bacteriological and pharmacological basis for H. pylori therapy and the current recommendations. The third-line treatment must be based on clarithromycin susceptibility testing. If the bacteria are still susceptible, failure may come from problems of compliance, hyperacidity or high bacterial load which can be overcome. If the bacteria are resistant, different regimens must be considered, including bismuth and non-bismuth-based quadruple therapies (sequential or concomitant), as well as triple therapies where amoxicillin is administered several times a day to obtain an optimal concentration at the gastric mucosal level. The treatments are becoming more and more complex and ecologically unsatisfactory, waiting for new agents or vaccines.     

Optimal airway antimicrobial therapy for cystic fibrosis: the role of inhaled aztreonam lysine

Importance of the field: Chronic endobronchial infection in cystic fibrosis (CF) leads to progressive lung function loss and respiratory failure. Most adult CF patients are infected with Pseudomonas aeruginosa, an important predictor of mortality. Suppressing chronic P. aeruginosa infection with inhaled antibiotics is standard of care for CF patients.

Areas covered in this review: This review describes the development (2003 – 2010) of aztreonam lysine 75 mg powder and solvent for nebulizer solution (AZLI; Cayston^®), an aerosolized formulation of the monobactam antibiotic aztreonam.

What the reader will gain: AZLI was studied in patients with CF and chronic P. aeruginosa airway infection. In placebo-controlled trials, AZLI improved respiratory symptoms, increased forced expiratory volume in 1 sec (FEV₁), decreased sputum P. aeruginosa density, and was well tolerated. An open-label follow-on trial of nine ‘on/off’ courses showed that AZLI was safe and the effect durable with repeated administration. AZLI was recently approved for use in CF patients in Australia and the USA, and conditionally approved in Canada and the European Union. AZLI is given three times daily for 28 days (2 – 3 min/dose), followed by 28 days off-drug. AZLI is used only with the Altera Nebulizer System?, which provides appropriate particle size and small airway deposition, and has excellent portability.

Take home message: AZLI is a new therapy that is safe and effectively improves respiratory symptoms and FEV₁ in patients with CF.     

Use of adjuvants in the treatment of Acinetobacter baumannii

The current antibiotic crisis to treat infections by Acinetobacter baumannii is linked with the increase of antimicrobial resistance and the lack of development of new antimicrobial drugs. For this reason, new alternatives for the treatment and control of infections by A. baumannii are necessary. Several studies have reported the effect of adjuvants to restore the efficacy of existing antimicrobial agents. Herein, we analyzed the main results on the development of adjuvant drugs, as monotherapy or in combination therapy with existing antimicrobial agents, which have shown promising results in vitro and in vivo. However, caution is needed and further extensive in vivo studies have to be performed to confirm the potential use of these adjuvants as true therapeutic alternatives.     

An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs

Introduction: The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds.

Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules.

Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.     

4238份血培养标本的病原菌分布情况及耐药性研究

目的对该院2012年6月至2016年6月血培养标本中病原菌分布情况及耐药性的研究。方法选用BD Bactec FX-200血培养分析仪对2012年6月至2016年6月共4 238份标本进行检测并对鉴定结果进行回顾性分析。结果 4 238份血培养标本中检测出阳性标本455株,阳性率为10.74%,革兰阳性菌占38.02%,革兰阴性菌占60.00%,真菌占1.98%;主要分布在新生儿和中老年患者中,分别为6.78%和76.17%。其中肠杆菌科占54.10%,以大肠埃希菌和肺炎克雷伯菌为主,非发酵菌占2.90%。革兰阳性球菌以葡萄球菌属为主,占25.87%。肠杆菌科对美罗培南、亚胺培南等较为敏感,非发酵菌对哌拉西林/他唑巴坦较为敏感,葡萄球菌和链球菌对万古霉素较为敏感。结论结合患者病原菌分布及耐药情况,临床医生应合理用药增强菌血症和真菌血症的治愈率。     

MEROPENEM IN THE TREATMENT OF FEBRILE NEUTROPENIC CHILDREN

The aim of this retrospective study was to evaluate the clinical effectiveness of meropenem in immunocompromised children. Between January 1998 and December 2002 in the hemato-oncological units of our hospital meropenem was used in 87 febrile events diagnosed in 55 patients, and 328 bacterial cultures were evaluated. Microorganisms were detected and identified in 64 of the 328 hemocultures; there was a predominance of gram-positive strains (67%). In 49.4% the infection was documented microbiologically. In 16 additional cases the infection was proven clinically and 32.2% of the episodes were considered to be fever of unknown origin. The success rate of the meropenem therapy—excluding the proven fungal or coagulase-negative Staphylococcus infections—was 72.9% and for the whole cohort 49.4%. The results demonstrate that meropenem is effective and well-tolerated when used for the treatment of neutropenic cancer children.     

Antibiotic resistance in hospitals: a ward‐specific random effect model in a low antibiotic consumption environment

Association between previous antibiotic use and emergence of antibiotic resistance has been reported for several microorganisms. The relationship has been extensively studied, and although the causes of antibiotic resistance are multi‐factorial, clear evidence of antibiotic use as a major risk factor exists. Most studies are carried out in countries with high consumption of antibiotics and corresponding high levels of antibiotic resistance, and currently, little is known whether and at what level the associations are detectable in a low antibiotic consumption environment. We conduct an ecological, retrospective study aimed at determining the impact of antibiotic consumption on antibiotic‐resistant Pseudomonas aeruginosa in three hospitals in Norway, a country with low levels of antibiotic use. We construct a sophisticated statistical model to capture such low signals. To reduce noise, we conduct our study at hospital ward level. We propose a random effect Poisson or binomial regression model, with a reparametrisation that allows us to reduce the number of parameters. Inference is likelihood based. Through scenario simulation, we study the potential effects of reduced or increased antibiotic use. Results clearly indicate that the effects of consumption on resistance are present under conditions with relatively low use of antibiotic agents. This strengthens the recommendation on prudent use of antibiotics, even when consumption is relatively low. Copyright © 2012 John Wiley & Sons, Ltd.