Effectiveness of β lactam antibiotics compared with antibiotics active against atypical pathogens in non-severe community acquired pneumonia: meta-analysis

Objective To systematically compare β lactam antibiotics with antibiotics active against atypical pathogens in the management of community acquired pneumonia.Data sources Medline, Embase, Cochrane register of controlled trials, international conference proceedings, drug registration authorities, and pharmaceutical companies.Review methods Double blind randomised controlled monotherapy trials comparing β lactam antibiotics with antibiotics active against atypical pathogens in adults with community acquired pneumonia. Primary outcome was failure to achieve clinical cure or improvement.Results 18 trials totalling 6749 participants were identified, with most patients having mild to moderate community acquired pneumonia. The summary relative risk for treatment failure in all cause community acquired pneumonia showed no advantage of antibiotics active against atypical pathogens over β lactam antibiotics (0.97, 95% confidence interval 0.87 to 1.07). Subgroup analysis was undertaken in those with a specific diagnosis involving atypical pathogens. We found a significantly lower failure rate in patients with Legionella species who were treated with antibiotics active against atypical pathogens (0.40, 0.19 to 0.85). Equivalence was seen for Mycoplasma pneumoniae (0.60, 0.31 to 1.17) and Chlamydia pneumoniae (2.32, 0.67 to 8.03).Conclusions Evidence is lacking that clinical outcomes are improved by using antibiotics active against atypical pathogens in all cause non-severe community acquired pneumonia. Although such antibiotics were superior in the management of patients later shown to have legionella related pneumonia, this pathogen was rarely responsible for pneumonia within the included trials. β lactam agents should remain the antibiotics of initial choice in adults with non-severe community acquired pneumonia.     

Combination drugs, an emerging option for antibacterial therapy

The emerging and sustained resistance to antibiotics and the poor pipeline of new antibacterials is creating a major health issue worldwide. Bacterial pathogens are increasingly becoming resistant even to the most recently approved antibiotics. Few antibiotics are being approved by regulatory organizations, which reflects both the difficulty of developing such agents and the fact that antibiotic discovery programs have been terminated at several major pharmaceutical companies in the past decade. As a result, the output of the drug pipelines is simply not well positioned to control the growing army of resistant pathogens, although academic institutions and smaller companies are trying to fill that gap. An emerging option to fight such pathogens is combination therapy. Combinations of two antibiotics or antibiotics with adjuvants are emerging as a promising therapeutic approach. This article provides and discusses clinical and scientific challenges to support the development of combination therapy to treat bacterial infections.     

Bacterial Temporal Dynamics Enable Optimal Design of Antibiotic Treatment

There is a critical need to better use existing antibiotics due to the urgent threat of antibiotic resistant bacteria coupled with the reduced effort in developing new antibiotics. β-lactam antibiotics represent one of the most commonly used classes of antibiotics to treat a broad spectrum of Gram-positive and -negative bacterial pathogens. However, the rise of extended spectrum β-lactamase (ESBL) producing bacteria has limited the use of β-lactams. Due to the concern of complex drug responses, many β-lactams are typically ruled out if ESBL-producing pathogens are detected, even if these pathogens test as susceptible to some β-lactams. Using quantitative modeling, we show that β-lactams could still effectively treat pathogens producing low or moderate levels of ESBLs when administered properly. We further develop a metric to guide the design of a dosing protocol to optimize treatment efficiency for any antibiotic-pathogen combination. Ultimately, optimized dosing protocols could allow reintroduction of a repertoire of first-line antibiotics with improved treatment outcomes and preserve last-resort antibiotics.     

生防细菌产生的拮抗物质及其在生物防治中的作用

利用生防细菌防治植物病害是生物防治的一个主要内容．生防细菌防治植物病害发生发展的一个重要机制是产生拮抗物质．生防细菌的拮抗物质种类多,作用范围广谱．同一种拮抗物质可以由多种细菌菌株产生,而同一细菌也可以产生多种不同结构的拮抗物质．运用现代分子生物学技术和先进的分析测试手段可以加快对产生拮抗物质生防细菌的研究,了解生防细菌在寄主植物根围和叶围的定植效果。明确拮抗物质在生物防治中的作用．拮抗物质的产生除与细菌基因型有关外,一些外在的生物和非生物因素如病原菌存在与否、温度、pH和C、N营养等也影响拮抗物质产生．文中论述了生防细菌应用中存在的问题。指出混合菌剂的研制对防止病原菌抗性产生具有重要作用,应是今后生防菌剂研制中的重点．     

Antibiotic Resistance in Bacteria and Its Future for Novel Antibiotic Development

Since the first introduction of the sulfa drugs and penicillin into clinical use, large numbers of antibiotics have been developed and hence contributed to human health. But extensive use of antibiotics has raised a serious public health problem due to multiantibiotic resistant bacterial pathogens that inevitably develop resistance to every new drug launched in the clinic. Consequently, there is a pressing need to develop new antibiotics to keep pace with bacterial resistance. Recent advances in microbial genomics and X-ray crystallography provide opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics respectively. To prevent and control infectious diseases caused by multiantibiotic resistant bacteria, we need to understand more about the molecular aspects of the pathogens’ physiology and to pursue ways to prolong the life of precious antibiotics.     

Antimicrobials, drug discovery, and genome mining

Over the years, antibiotics have provided an effective treatment for a number of microbial diseases. However recently, there has been an increase in resistant microorganisms that have adapted to our current antibiotics. One of the most dangerous pathogens is methicillin-resistant Staphylococcus aureus (MRSA). With the rise in the cases of MRSA and other resistant pathogens such as vancomycin-resistant Staphylococcus aureus, the need for new antibiotics increases every day. Many challenges face the discovery and development of new antibiotics, making it difficult for these new drugs to reach the market, especially since many of the pharmaceutical companies have stopped searching for antibiotics. With the advent of genome sequencing, new antibiotics are being found by the techniques of genome mining, offering hope for the future.     

Hidden antibiotics: Where to uncover?

The struggle of humans versus pathogens is a never ending battle. Since the discovery of antibiotics humans have tipped the scales in their favour, but today bacteria are nullifying this advantage by developing resistance mechanisms against these molecules. The plethora of different antibiotics active against pathogens is shrinking while the discovery of new molecules is arduous. Especially the development of drugs active against Gram^? pathogens continues slowly. New strategies to discover novel, potent antibiotics are hence needed. Adopting the optimistic view of technological singularity, innovative and disruptive approaches are required and hence proposed to lift the current conundrum. In this review, questions are answered on where and how to look for new natural product hit molecules with antibacterial activity, on how the field of synthetic biology can aid the contemporary pharmaceutical challenge and whether we are ready to make the transition towards other approaches, such as narrow-spectrum antibiotics and phage therapy.     

Antibiotic resistance is prevalent in an isolated cave microbiome

Antibiotic resistance is a global challenge that impacts all pharmaceutically used antibiotics. The origin of the genes associated with this resistance is of significant importance to our understanding of the evolution and dissemination of antibiotic resistance in pathogens. A growing body of evidence implicates environmental organisms as reservoirs of these resistance genes; however, the role of anthropogenic use of antibiotics in the emergence of these genes is controversial. We report a screen of a sample of the culturable microbiome of Lechuguilla Cave, New Mexico, in a region of the cave that has been isolated for over 4 million years. We report that, like surface microbes, these bacteria were highly resistant to antibiotics; some strains were resistant to 14 different commercially available antibiotics. Resistance was detected to a wide range of structurally different antibiotics including daptomycin, an antibiotic of last resort in the treatment of drug resistant Gram-positive pathogens. Enzyme-mediated mechanisms of resistance were also discovered for natural and semi-synthetic macrolide antibiotics via glycosylation and through a kinase-mediated phosphorylation mechanism. Sequencing of the genome of one of the resistant bacteria identified a macrolide kinase encoding gene and characterization of its product revealed it to be related to a known family of kinases circulating in modern drug resistant pathogens. The implications of this study are significant to our understanding of the prevalence of resistance, even in microbiomes isolated from human use of antibiotics. This supports a growing understanding that antibiotic resistance is natural, ancient, and hard wired in the microbial pangenome.     

Targets and assays for discovering novel antibacterial agents

The increasing frequency of nosocomial infections due to multi-resistant pathogens exerts a significant toll and calls for novel and better antibiotics. Different approaches can be used in the search for novel antibiotics acting on drug-resistant bacterial pathogens. We present some considerations on valid bacterial targets to be used for searching new antibiotics, and how the information from bacterial genome sequences can assist in choosing the appropriate targets. Other factors to be considered in target selection are the chemical diversity available for screening and its uniqueness. We will conclude discussing our strategy for searching novel antibacterials. This is based on a large collection of microbial extracts as a source of chemical diversity and on the use of specific targets essential for the viability of bacterial pathogens. Two assay strategies have been implemented: a pathway-based assay, where a series of essential bacterial targets is screened in a single assay; and a binding assay, where many targets can be screened individually in the same format.     

新生儿感染性肺炎的病原茵状况分析

目的了解本地区新生儿感染性肺炎的病原菌的菌种、构成比及耐药情况,探索临床合理选用抗生素。方法细菌鉴定及药敏试验采用VITEK-60全自动细菌鉴定仪。结果本地区新生儿感染性肺炎的病原菌主要为革兰阴性杆菌（92．81％）,其中以肺炎克雷伯菌最为常见,革兰阳性球菌感染较少（7．19％）。革兰阴性杆菌对头孢二代、三代和氨基糖苷类抗生素的耐药率均较高,对喹诺酮类抗生素耐药率较低。亚胺培南具有良好的抗菌活性。结论肺炎克雷伯菌是本地区新生儿感染性肺炎的主要病原菌。经验性治疗用药可首选亚胺培南、头孢替坦、环丙沙星等,建议临床根据药敏结果选用抗生素。     

2002年至2007年太原地区儿童细菌性腹泻病原菌分布及耐药分析

目的了解太原地区近6年儿童细菌性腹泻病原菌分布及耐药情况。方法对临床诊断细菌性腹泻病,便培养已分离到病原菌1080例作回顾性分析,分析其病原菌的分布及耐药情况。结果埃希菌属486株（45％）,居于首位,前5位的病原菌依次为埃希菌属、肠球菌属、酵母样真菌、志贺菌属、假单胞菌属。各年均以大肠埃希菌为主要检出菌,志贺菌逐年减少。年龄分布中,婴儿的构成比最高（44．4％）。埃希菌属、志贺菌属、假单胞菌属、沙门菌属、气单胞菌属此5种杆菌对13种抗生素的平均耐药率依次为舒普深、痢特灵、头孢他啶、庆大霉素、环丙沙星、头孢哌酮、头孢曲松、丁胺卡那、头孢噻肟、诺氟沙星、头孢呋辛、哌拉西林、头孢唑啉。从埃希菌属近6年的耐药性变迁资料可以看出,对13种抗生素的耐药率均有不同程度上升。结论传统的致病菌志贺菌属、沙门菌属较少,而肠球菌属、假单胞菌属、枸橼酸杆菌属、克雷伯杆菌属、肠杆菌属、酵母样真菌等条件致病菌肠炎占有相当比例。各种致病菌的耐药性增加,第三代头孢除头孢他啶的耐药率较低外,其余都较高。提示应严格掌握抗生素用药指证,合理选用抗生素。     

Crossroads of Antibiotic Resistance and Biosynthesis

The biosynthesis of antibiotics and self-protection mechanisms employed by antibiotic producers are an integral part of the growing antibiotic resistance threat. The origins of clinically relevant antibiotic resistance genes found in human pathogens have been traced to ancient microbial producers of antibiotics in natural environments. Widespread and frequent antibiotic use amplifies environmental pools of antibiotic resistance genes and increases the likelihood for the selection of a resistance event in human pathogens. This perspective will provide an overview of the origins of antibiotic resistance to highlight the crossroads of antibiotic biosynthesis and producer self-protection that result in clinically relevant resistance mechanisms. Some case studies of synergistic antibiotic combinations, adjuvants, and hybrid antibiotics will also be presented to show how native antibiotic producers manage the emergence of antibiotic resistance.     

Antibiotics and the resistant microbiome

Since the discovery and clinical application of antibiotics, pathogens and the human microbiota have faced a near continuous exposure to these selective agents. A well-established consequence of this exposure is the evolution of multidrug-resistant pathogens, which can become virtually untreatable. Less appreciated are the concomitant changes in the human microbiome in response to these assaults and their contribution to clinical resistance problems. Studies have shown that pervasive changes to the human microbiota result from antibiotic treatment and that resistant strains can persist for years. Additionally, culture-independent functional characterization of the resistance genes from the microbiome has demonstrated a close evolutionary relationship between resistance genes in the microbiome and in pathogens. Application of these techniques and novel cultivation methods are expected to significantly expand our understanding of the interplay between antibiotics and the microbiome.     

儿童泌尿系感染的病原学分析

探讨目前儿童泌尿系感染病原体的变化趋势,为临床治疗提供实验依据。分析2008年1月至2009年10月住院治疗的357例尿细菌培养、支原体体外培养、衣原体检测阳性的泌尿系感染患儿病原体的分布情况。结果显示,尿细菌培养和支原体体外培养、衣原体检测前未应用过抗生素的患儿其阳性率为82.2%,而应用过抗生素的患儿其阳性率为31.8%,两者相比具有统计学意义(P0.01)。在检测的357例阳性标本中,革兰阴性杆菌占74.7%,其中以大肠埃希菌为主,占46.2%;革兰阳性球菌占14.8%,其中肠球菌占10.9%;真菌占3.1%,支原体占4.8%,衣原体占2.5%。临床要密切关注儿童泌尿系感染病原体的分布变迁情况,以便于为临床的诊断和治疗提供可靠的实验依据。     

The role of antibiotics and antibiotic resistance in nature

Investigations of antibiotic resistance from an environmental prospective shed new light on a problem that was traditionally confined to a subset of clinically relevant antibiotic‐resistant bacterial pathogens. It is clear that the environmental microbiota, even in apparently antibiotic‐free environments, possess an enormous number and diversity of antibiotic resistance genes, some of which are very similar to the genes circulating in pathogenic microbiota. It is difficult to explain the role of antibiotics and antibiotic resistance in natural environments from an anthropocentric point of view, which is focused on clinical aspects such as the efficiency of antibiotics in clearing infections and pathogens that are resistant to antibiotic treatment. A broader overview of the role of antibiotics and antibiotic resistance in nature from the evolutionary and ecological prospective suggests that antibiotics have evolved as another way of intra‐ and inter‐domain communication in various ecosystems. This signalling by non‐clinical concentrations of antibiotics in the environment results in adaptive phenotypic and genotypic responses of microbiota and other members of the community. Understanding the complex picture of evolution and ecology of antibiotics and antibiotic resistance may help to understand the processes leading to the emergence and dissemination of antibiotic resistance and also help to control it, at least in relation to the newer antibiotics now entering clinical practice.     

Isolation and partial characterization of Salmonella Gallinarum bacteriophage

Infections caused by Salmonella remain a major public health problem worldwide. Animal food products, including poultry meat and eggs, are considered essential components in the individual’s daily nutrition. However, chicken continues to be the main reservoir for Salmonella spp.Poultry farmers use several types of antibiotics to treat pathogens. This can pose a health risk as pathogens can build antibiotic resistance in addition to the possibility of accumulation of these antibiotics in food products. The use of phages in treating poultry pathogens is increasing worldwide due to its potential use as an effective alternative to antibiotics. Phages have several advantages over antibiotics; phages are very specific to target bacteria, less chances of developing secondary infections, and they only replicate at the site of infection.Here we report the isolation of a bacteriophage from chicken feces. The isolated bacteriophage hosts on Salmonella Gallinarum, a common zoonotic infection that causes fowl typhoid, known to cause major losses to poultry sector. The isolated bacteriophage was partially characterized as a DNA virus resistant to RNase digestion with approximately 20 Kb genome. SDS-PAGE analysis of total viral proteins showed at least five major bands (21, 28, 42, 55 and 68 kDa), indicating that this virus is relatively small compared to other known poultry phages. The isolated bacteriophage has the potential to be an alternative to antibiotics and possibly reducing antibiotic resistance in poultry farms.     

肾综合征出血热少尿期的肺部感染菌群分布及其耐药分析

目的了解肾综合征出血热少尿期的肺部细菌感染对临床治疗的意义。方法送检的所有痰液标本按常规方法进行细菌分离鉴定,药敏试验为K-B法,ESBLs以双纸片协同试验进行,MRS检测为纸片筛选法。结果痰液标本338份,细菌培养检出率68.9%,革兰阴性菌占优势,以铜绿假单胞菌、大肠埃希菌、肺炎克雷伯菌为主。对碳青霉烯类、头孢哌酮/他唑巴坦均分别低于9.09%、12.5%,头孢吡肟为27.4%,其余抗生素的耐药率均高于31.3%。3种主要产ESBLs菌对碳青霉烯类、头孢哌酮/他唑巴坦均分别低于15.8%、17.2%,其余抗生素的耐药率均高于55.2%。革兰阳性菌主要以金黄色萄葡球菌为主。结论肺部感染以革兰阴性菌占优势,碳青霉烯类、头孢哌酮/他唑巴坦是抗感染治疗的首选药物。     

457株尿路感染的病原菌及其耐药性研究

目的了解尿路感染的病原菌分布及耐药情况,为临床合理用药提供依据。方法用VITEK-AMS微生物自动分析仪鉴定菌种和药敏试验,同时对大肠埃希菌和肺炎克雷伯菌进行ESBLs检测,对肠球菌进行氨基糖苷类高水平耐药（HLAR）的筛选。结果尿路感染以大肠埃希菌检出率最高（50．5％）其余依次为肠球菌属（10．5％）,克雷伯菌属（8．6％）,真菌（7．9％）等,大肠埃希菌和肺炎克雷伯菌ESBLs检出率分别为24．2％和17．9％,HLAR肠球菌检出率为60．4％．尿路感染病原菌对喹诺酮类等常用药物的耐药性较高。结论明确尿路感染的病原菌及其耐药性对合理使用抗生素具有重要意义。     

Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida

Macrolides have been effective clinical antibiotics for over 70 years. They inhibit protein biosynthesis in bacterial pathogens by narrowing the nascent protein exit tunnel in the ribosome. The macrolide class of natural products consist of a macrolactone ring linked to one or more sugar molecules. Most of the macrolides used currently are semi-synthetic erythromycin derivatives, composed of a 14- or 15-membered macrolactone ring. Rapidly emerging resistance in bacterial pathogens is among the most urgent global health challenges, which render many antibiotics ineffective, including next-generation macrolides. To address this threat and advance a longer-term plan for developing new antibiotics, we demonstrate how 16-membered macrolides overcome erythromycin resistance in clinically isolated Staphylococcus aureus strains. By determining the structures of complexes of the large ribosomal subunit of Deinococcus radiodurans (D50S) with these 16-membered selected macrolides, and performing anti-microbial studies, we identified resistance mechanisms they may overcome. This new information provides important insights toward the rational design of therapeutics that are effective against drug resistant human pathogens.     

非免疫抑制患者医院获得性肺炎及呼吸机相关肺炎病原菌组成及耐药性分析

目的分析非免疫抑制患者医院获得性肺炎及呼吸机相关肺炎临床特征、病原菌组成及耐药性,指导临床诊断及合理使用抗菌素。方法回顾性分析46例前瞻性观察诊断的非免疫抑制患者医院获得性肺炎及呼吸机相关肺炎临床及微生物学资料。结果平均起病时间为人院后（14．3±13．2）d,最常见基础疾病依次为脑血管意外（16／46）,慢性肺部疾病（13／46）和糖尿病（5／46）。培养阳性率58．7％,最常见细菌依次为鲍曼不动杆菌（8／27）、铜绿假单胞菌（6／27）、阴沟肠杆菌（3／29）及金黄色葡萄球菌（3／29）。80．4％患者入院72h内使用过抗生素,初始经验性治疗最常使用的抗菌素依次为头孢菌素（29／46）、碳青霉烯类（9／46）、糖肽类（5／46）。8株鲍曼不动杆菌对头孢哌酮／舒巴坦中介MIC〉32mg／L,对其他抗生素耐药;2株铜绿假单胞菌对美罗培南高度耐药MIC=128mg／L。结论非免疫抑制患者医院获得性肺炎及呼吸机相关肺炎多发生在有脑血管疾病及慢性肺疾病老年患者,我院非免疫抑制患者医院获得性肺炎及呼吸机相关肺炎最常见的病原菌多药耐药鲍曼不动杆菌,铜绿假单胞菌对碳青霉烯类耐药率较高。应优化医院获得性肺炎及呼吸机相关肺炎初始抗生素使用。