Antimicrobial resistance in foodborne pathogens--a cause for concern?

The widespread use of antibiotics in food animal production systems has resulted in the emergence of antibiotic resistant zoonotic bacteria that can be transmitted to humans through the food chain. Infection with antibiotic resistant bacteria negatively impacts on public health, due to an increased incidence of treatment failure and severity of disease. Development of resistant bacteria in food animals can result from chromosomal mutations but is more commonly associated with the horizontal transfer of resistance determinants borne on mobile genetic elements. Food may represent a dynamic environment for the continuing transfer of antibiotic resistance determinants between bacteria. Current food preservation systems that use a combination of environmental stresses to reduce growth of bacteria, may serve to escalate development and dissemination of antibiotic resistance among food related pathogens. The increasing reliance on biocides for pathogen control in food production and processing, heightens the risk of selection of biocide-resistant strains. Of particular concern is the potential for sublethal exposure to biocides to select for bacteria with enhanced multi-drug efflux pump activity capable of providing both resistance to biocides and cross-resistance to multiple antibiotics. Although present evidence suggests that biocide resistance is associated with a physiological cost, the possibility of the development of adaptive mutations conferring increased fitness cannot be ruled-out. Strategies aimed at inhibiting efflux pumps and eliminating plasmids could help to restore therapeutic efficacy to antibiotics and reduce the spread of antibiotic resistant foodborne pathogens through the food chain.     

Exploiting a conjugative CRISPR/Cas9 system to eliminate plasmid harbouring the mcr-1 gene from Escherichia coli

The transfer of multi-drug-resistance plasmids by bacterial conjugation is largely responsible for the development of drug resistance in bacteria, and causes serious problems in the treatment of infectious diseases. Since the first discovery of plasmid-borne colistin resistance gene mcr-1 was reported in late 2016, this gene has been found in a great number of Escherichia coli and other Gram-negative pathogens separated from different types of sources worldwide. The elimination of plasmids carrying mcr-1 and restoration of polymyxin sensitivity has very important clinical significance because polymyxins are frequently used as last-resort antibiotics to treat extensively drug-resistant Gram-negative bacterial infections. A host-independent conjugative plasmid was constructed in this study, and an engineered CRISPR/Cas9 system was used to remove plasmid harbouring mcr-1 from bacteria. This study found that this conjugative plasmid can not only be used as a new tool to remove resistance plasmids and sensitize the recipient bacteria to antibiotics, but can also make the recipient cell acquire immunity against mcr-1. This strategy provides a novel method to counteract the ever-worsening spread of mcr-1 among bacterial pathogens.     

Antibiotic usage in animals: impact on bacterial resistance and public health.

Antibiotic use whether for therapy or prevention of bacterial diseases, or as performance enhancers will result in antibiotic resistant micro-organisms, not only among pathogens but also among bacteria of the endogenous microflora of animals. The extent to which antibiotic use in animals will contribute to the antibiotic resistance in humans is still under much debate. In addition to the veterinary use of antibiotics, the use of these agents as antimicrobial growth promoters (AGP) greatly influences the prevalence of resistance in animal bacteria and a poses risk factor for the emergence of antibiotic resistance in human pathogens. Antibiotic resistant bacteria such as Escherichia coli, Salmonella spp., Campylobacter spp. and enterococci from animals can colonise or infect the human population via contact (occupational exposure) or via the food chain. Moreover, resistance genes can be transferred from bacteria of animals to human pathogens in the intestinal flora of humans. In humans, the control of resistance is based on hygienic measures: prevention of cross contamination and a decrease in the usage of antibiotics. In food animals housed closely together, hygienic measures, such as prevention of oral-faecal contact, are not feasible. Therefore, diminishing the need for antibiotics is the only possible way of controlling resistance in large groups of animals. This can be achieved by improvement of animal husbandry systems, feed composition and eradication of or vaccination against infectious diseases. Moreover, abolishing the use of antibiotics as feed additives for growth promotion in animals bred as a food source for humans would decrease the use of antibiotics in animals on a worldwide scale by nearly 50%. This would not only diminish the public health risk of dissemination of resistant bacteria or resistant genes from animals to humans, but would also be of major importance in maintaining the efficacy of antibiotics in veterinary medicine.     

Mutation and evolution of antibiotic resistance: antibiotics as promoters of antibiotic resistance?

Antibiotic resistance appearance and spread have been classically considered the result of a process of natural selection, directed by the use of antibiotics. Bacteria, that have to face the antibiotic challenge, evolve to acquire resistance and, under this strong selective pressure, only the fittest survive, leading to the spread of resistance mechanisms and resistant clones. Horizontal transference of resistance mechanisms seems to be the main way of antibiotic resistance acquisition. Nevertheless, recent findings on hypermutability and antibiotic-induced hypermutation in bacteria have modified the landscape. Here, we present a review of the last data on molecular mechanisms of hypermutability in bacteria and their relationship with the acquisition of antibiotic resistance. Finally, we discuss the possibility that antibiotics may act not only as selectors for antibiotic resistant bacteria but also as resistance promoters.     

Plasmid encoded antibiotic resistance: acquisition and transfer of antibiotic resistance genes in bacteria

Bacteria have existed on Earth for three billion years or so and have become adept at protecting themselves against toxic chemicals. Antibiotics have been in clinical use for a little more than 6 decades. That antibiotic resistance is now a major clinical problem all over the world attests to the success and speed of bacterial adaptation. Mechanisms of antibiotic resistance in bacteria are varied and include target protection, target substitution, antibiotic detoxification and block of intracellular antibiotic accumulation. Acquisition of genes needed to elaborate the various mechanisms is greatly aided by a variety of promiscuous gene transfer systems, such as bacterial conjugative plasmids, transposable elements and integron systems, that move genes from one DNA system to another and from one bacterial cell to another, not necessarily one related to the gene donor. Bacterial plasmids serve as the scaffold on which are assembled arrays of antibiotic resistance genes, by transposition (transposable elements and ISCR mediated transposition) and site-specific recombination mechanisms (integron gene cassettes).The evidence suggests that antibiotic resistance genes in human bacterial pathogens originate from a multitude of bacterial sources, indicating that the genomes of all bacteria can be considered as a single global gene pool into which most, if not all, bacteria can dip for genes necessary for survival. In terms of antibiotic resistance, plasmids serve a central role, as the vehicles for resistance gene capture and their subsequent dissemination. These various aspects of bacterial resistance to antibiotics will be explored in this presentation.     

Bacterial targets to antimicrobial leads and development candidates

The unabated spread of drug-resistant bacterial pathogens continues to pose a significant threat to patient health. However, there are now several new and improved derivatives from established classes of antibiotics that have recently been approved or are in late-stage development. In drug discovery, screening of new targets derived from genomic-based discovery stratagems has resulted in a number of potent antibacterial leads. Further optimization and development of these promising compounds offer the opportunity to develop new classes of antimicrobials that act through modes of action that are unlikely to be affected by resistance mechanisms defined to date. In addition, new discoveries in biochemical mechanisms of antibiotic action continue to help identify new approaches to design novel antibiotic analogs.     

Review article: antibiotics and the gut

Antibiotics have an important place in the management of gastrointestinal disease. Recent studies have demonstrated efficacy in acute bacterial gastroenteritis caused by salmonellae and campylobacteriaceae, shigellae and enterotoxigenic strains of E coli (ETEC). Tetracycline remains effective in cholera. Antibiotic resistance is widespread amongst the enteric pathogens and can quickly spread during epidemics of infective diarrhoeas. It is important that antibiotics are reserved for the treatment of serious infections lest their effectiveness in these conditions be lost. Campylobacter pylori appears to be an important cause of chronic active gastritis and is amenable to treatment with antibiotics and bismuth salts. The role of C. pylori in the pathogenesis of peptic ulcer disease is not yet established but there is mounting evidence that antibiotic treatment will have a place in the treatment of this common condition. The effect of antibiotics on the normal intestinal microflora can have serious consequences. It is a major cause of resistance in urinary tract pathogens, can result in outbreaks of hospital infection with resistant organisms and frequently results in C. difficile associated diarrhoea.     

呼吸道感染者的细菌培养及抗生素耐药情况分析

目的通过对呼吸道感染细菌培养及抗生素耐药情况分析,以期正确、合理及有效使用抗生素。方法选取180例呼吸道感染者且进行细菌培养和抗生素耐药率统计,然后对所得数据给予相应统计学处理,最后对其结果进行合理分析。结果革兰阳性菌占28.33%、革兰阴性菌占71.67%且革兰阴性菌明显高于革兰阳性菌,同时对常规抗生素存在不同程度的耐药性。结论做好呼吸道感染病原菌的监测及耐药性分析对临床合理选取抗生素至关重要。     

Antibiotic-containing polymers for localized,sustained drug delivery

Many currently used antibiotics suffer from issues such as systemic toxicity, short half-life, and increased susceptibility to bacterial resistance. Although most antibiotic classes are administered systemically through oral or intravenous routes, a more efficient delivery system is needed. This review discusses the chemical conjugation of antibiotics to polymers, achieved by forming covalent bonds between antibiotics and a pre-existing polymer or by developing novel antibiotic-containing polymers. Through conjugating antibiotics to polymers, unique polymer properties can be taken advantage of. These polymeric antibiotics display controlled, sustained drug release and vary in antibiotic class type, synthetic method, polymer composition, bond lability, and antibacterial activity. The polymer synthesis, characterization, drug release, and antibacterial activities, if applicable, will be presented to offer a detailed overview of each system.     

ICU患者下呼吸道感染的细菌分布和耐药性分析

目的探讨ICU患者下呼吸道感染细菌分布特征及耐药性分析。方法收集我院2008年10月至2010年10月间ICU病房患者240例痰液标本进行菌株鉴定和药敏实验。结果 240例患者痰液标本分离出病原菌210例,阳性率占75%。其中革兰阴性杆菌占70%,革兰阴性球菌占21%,真菌占9%,以铜绿假单胞菌居首位,其次为金黄色葡萄球菌,肺炎克雷伯氏菌,不动杆菌属和真菌。结论革兰阴性杆菌为ICU病房患者医院感染主要病原菌,对常用抗菌药呈高度耐药特征,并有上升趋势。根据细菌培养及药物敏感实验合理选用抗菌药物,是防止抗菌素滥用,控制院内感染病原传播的关键。     

南京地区新生儿血培养病原菌分布及耐药性分析

目的:了解南京地区新生儿败血症病原菌分布及其耐药情况,为临床合理选择抗生素提供参考。方法:收集2009年1月-2011年9月我院住院新生儿血培养标本1546例,分析其病原菌分布及耐药性。结果:1546例新生儿血培养标本共检出细菌186株,总阳性率为12.03%,因无临床表现支持而被视为假菌血症者7例,污染率为3.76%(7/186)。其中革兰阳性菌129株,占总分离菌的72.07%,革兰阳性菌以凝固酶阴性葡萄球菌为主,占革兰阳性菌的76.74%,占总分离菌的55.31%;革兰阴性菌50株,占总分离菌的27.93%,革兰阴性菌以肺炎克雷伯菌居多,占革兰阴性菌的42.00%,占总分离菌的11.73%。革兰阳性菌对抗生素耐药率最高的为青霉素,其次为红霉素,对万古霉素、哌拉西林/他唑巴坦、阿米卡星以及左氧氟沙星表现了较低的耐药率;革兰阴性菌对抗生素耐药率最高的为氨苄西林,其次为哌拉西林、头孢唑林、氨曲南,对亚胺培南、头孢吡肟、阿米卡星、左氧氟沙星以及加酶抑制剂的复合制剂表现了较低的耐药率。结论:凝固酶阴性葡萄球菌是南京地区近2年新生儿败血症最常见的病原菌,其次为肺炎克雷伯菌,对常用抗生素均有不同程度的耐药。     

湖北省部分三级医院铜绿假单胞菌耐药性变迁调查分析

目的 调查2002～2005年湖北地区铜绿假单胞菌的耐药性及流行趋势，为临床提供诊疗依据。方法 采用WHONET4,5软件对6 208株铜绿假单胞菌株的耐药率进行统计分析，所有菌株分离自湖北地区17所三级医院成人患者2002～2005年的各类临床标本。结果 4 a中湖北地区铜绿假单胞菌对常用抗菌药物的耐药率总体持平或小幅度上升，2005年铜绿假单胞菌对碳青霉烯类药物亚胺培南和美罗培南耐药率分别为25%和23%，略低于中国CHINET细菌耐药性监测结果。结论 坚持细菌耐药性的监测与公示、合理使用抗菌药物，对控制耐药菌的传播与流行具有重要意义。     

Practical applications and feasibility of efflux pump inhibitors in the clinic--a vision for applied use

The world of antibiotic drug discovery and development is driven by the necessity to overcome antibiotic resistance in common Gram-positive and Gram-negative pathogens. However, the lack of Gram-negative activity among both recently approved antibiotics and compounds in the developmental pipeline is a general trend despite the fact that the plethora of covered drug targets are well-conserved across the bacterial kingdom. Such intrinsic resistance in Gram-negative bacteria is largely attributed to the activity of multidrug resistance (MDR) efflux pumps. Moreover, these pumps also play a significant role in acquired clinical resistance. Together, these considerations make efflux pumps attractive targets for inhibition in that the resultant efflux pump inhibitor (EPI)/antibiotic combination drug should exhibit increased potency, enhanced spectrum of activity and reduced propensity for acquired resistance. To date, at least one class of broad-spectrum EPI has been extensively characterized. While these efforts indicated a significant potential for developing small molecule inhibitors against efflux pumps, they did not result in a clinically useful compound. Stemming from the continued clinical pressure for novel approaches to combat drug resistant bacterial infections, second-generation programs have been initiated and show early promise to significantly improve the clinical usefulness of currently available and future antibiotics against otherwise recalcitrant Gram-negative infections. It is also apparent that some changes in regulatory decision-making regarding resistance would be very helpful in order to facilitate approval of agents aiming to reverse resistance and prevent its further development.     

重症寻常型天疱疮严重皮肤感染的病原学分析及抗菌药物治疗

目的探讨重症寻常型天疱疮合并严重皮肤感染病原菌和耐药性,找出敏感抗生素并及时联合激素应用,以提高临床治疗水平。方法随机选取2011年1月至2013年3月61例重症寻常型天疱疮患者为研究对象,对其中伴有严重皮肤感染39的患者进行病原菌和耐药性分析。结果对病原菌分布进行比较,共分离出病原菌52株,其中革兰阴性菌占全部病原菌48．08％,革兰阳性菌占全部病原菌30．77％,真菌占21．15％。在革兰阴性菌中耐药性较低的抗菌药物有利福平、亚胺培南,均为0,而在革兰阳性菌中耐药性较低的抗生素为替考拉宁、万古霉素,均为0,真菌中耐药性较低的抗生素为5-氟胞嘧啶、两性霉素B,均为0。经一系列对症治疗后总有效率为66．67％,死亡率20．51％。结论重症寻常型天疱疮合并严重皮肤感染病原菌较为均匀,选择敏感抗生素可提高临床效果。     

Epidemiology of resistance to antibiotics. Links between animals and humans

An inevitable side effect of the use of antibiotics is the emergence and dissemination of resistant bacteria. Most retrospective and prospective studies show that after the introduction of an antibiotic not only the level of resistance of pathogenic bacteria, but also of commensal bacteria increases. Commensal bacteria constitute a reservior of resistance genes for (potentially) pathogenic bacteria. Their level of resistance is considered to be a good indicator for selection pressure by antibiotic use and for resistance problems to be expected in pathogens. Resistant commensal bacteria of food animals might contaminate, like zoonotic bacteria, meat (products) and so reach the intestinal tract of humans. Monitoring the prevalence of resistance in indicator bacteria such as faecal Escherichia coli and enterococci in different populations, animals, patients and healthy humans, makes it feasible to compare the prevalence of resistance and to detect transfer of resistant bacteria or resistance genes from animals to humans and vice versa. Only in countries that use or used avoparcin (a glycopeptide antibiotic, like vancomycin) as antimicrobial growth promoter (AMGP), is vancomycin resistance common in intestinal enterococci, not only in exposed animals, but also in the human population outside hospitals. Resistance genes against antibiotics, that are or have only been used in animals, i.e. nourseothricin, apramycin etc. were found soon after their introduction, not only in animal bacteria but also in the commensal flora of humans, in zoonotic pathogens like salmonellae, but also in strictly human pathogens, like shigellae. This makes it clear that not only clonal spread of resistant strains occurs, but also transfer of resistance genes between human and animal bacteria. Moreover, since the EU ban of avoparcin, a significant decrease has been observed in several European countries in the prevalence of vancomycin resistant enterococci in meat (products), in faecal samples of food animals and healthy humans, which underlines the role of antimicrobial usage in food animals in the selection of bacterial resistance and the transport of these resistances via the food chain to humans. To safeguard public health, the selection and dissemination of resistant bacteria from animals should be controlled. This can only be achieved by reducing the amounts of antibiotics used in animals. Discontinuing the practice of routinely adding AMGP to animal feeds would reduce the amounts of antibiotics used for animals in the EU by a minimum of 30% and in some member states even by 50%.     

Optimizing antimicrobial prescribing

Antibiotics are universally prescribed drugs. Because they exert selective pressure and because of the innate bacterial ability for adaptation, even the appropriate clinical use of these potentially life-preserving agents inevitably fosters the development and spread of resistance by a variety of microorganisms. Inappropriate use has accelerated and increased the magnitude of a problem that is now considered a public health crisis. For Gram-positive pathogens some compounds offer limited hope, but for Gram-negative organisms no new drugs with radically increased spectra are available for clinical trials. Patients with serious infections due to multiresistant organisms are experiencing adverse, sometimes fatal, clinical outcomes. Use of multiple drugs increases side effects and exposes additional susceptible bacteria to selective pressure. There is evidence that the appropriate use of currently available antibiotics can be associated with a reduction of the spread of resistance. Antibiotic stewardship programmes and the antibiotic 'care bundle' approach can be effective measures to lengthen the useful life of antibiotics and can be implemented in most clinical situations.     

Beyond serial passages: new methods for predicting the emergence of resistance to novel antibiotics

Market launching of a new antibiotic requires knowing in advance its benefits and possible risks, and among them how rapidly resistance will emerge and spread among bacterial pathogens. This information is not only useful from a public health point of view, but also for pharmaceutical industry, in order to reduce potential waste of resources in the development of a compound that might be discontinued at the short term because of resistance development. Most assays currently used for predicting the emergence of resistance are based on culturing the target bacteria by serial passages in the presence of increasing concentrations of antibiotics. Whereas these assays may be valuable for identifying mutations that might cause resistance, they are not useful to establish how fast resistance might appear, neither to address the risk of spread of resistance genes by horizontal gene transfer. In this article, we review recent information pertinent for a more accurate prediction on the emergence and dispersal of antibiotic resistance.     

人类肠道菌群中抗生素耐药基因的研究进展

抗生素耐药性在细菌病原体中不断出现并蔓延,其遗传物质基础抗生素耐药基因(ARG)可通过基因突变或水平基因转移等方式获得,并赋予宿主对抗生素的耐药性,从而严重威胁人类的健康.人类肠道菌群作为ARG产生和传播的重要场所越来越受到重视.人类肠道菌群含众多种类的ARG,可通过水平基因转移等方式实现ARG的传播.影响肠道菌群中A...     

下呼吸道感染革兰阴性杆菌的菌群分布及耐药性分析

目的了解下呼吸道感染革兰阴性杆菌的常见细菌分布及耐药性情况。以协助临床合理应用抗菌药物。方法对2009年1月至2010年5月住院患者下呼吸道感染痰标本所分离的病原菌,进行菌种和耐药性回顾性统计分析。结果共收集1354株细菌,其中革兰阴性杆菌1095株,占80.87%。革兰阴性杆菌中分离率占前五位的分别是：铜绿假单胞菌250株（占18.46%）,鲍曼不动杆菌182株（占13.44%）,肺炎克雷伯菌株158株（占11.67%）,大肠埃希菌143株（占10.56%）,嗜麦芽黄单孢菌86株（占6.35%）。主要革兰阴性杆菌均耐药,对抗菌药物耐药率普遍较高的细菌为鲍曼不动杆菌、肺炎克雷伯菌,大肠埃希菌。结论呼吸道分离的革兰阴性杆菌均存在严重耐药问题,及时监测病原菌变化及耐药趋势以指导临床用药至关重要。