Farm animals and aquaculture: significant reservoirs of mobile colistin resistance genes

Colistin resistance has attracted substantial attention after colistin was considered as a last-resort drug for the treatment of infections caused by carbapenem-resistant and/or multidrug-resistant (MDR) Gram-negative bacteria in clinical settings. However, with the discovery of highly mobile colistin resistance (mcr) genes, colistin resistance has become an increasingly urgent issue worldwide. Despite many reviews, which summarized the prevalence, mechanisms, and structures of these genes in bacteria of human and animal origin, studies on the prevalence of mobile colistin resistance genes in aquaculture and their transmission between animals and humans remain scarce. Herein, we review recent reports on the prevalence of colistin resistance genes in animals, especially wildlife and aquaculture, and their possibility of transmission to humans via the food chain. This review also gives some insights into the routine surveillance, changing policy and replacement of polymyxins by polymyxin derivatives, molecular inhibitors, and traditional Chinese medicine to tackle colistin resistance.     

沙门氏菌抗生素抗性机理研究进展

沙门氏菌的多重耐药性问题已经成为世界范围内的公共卫生和经济问题.目前沙门氏菌抗生素抗性机理的研究主要集中以下方面:(1)基因突变与抗生素抗性;(2)外排泵与抗生素抗性:(3)耐药基因编码的钝化酶和灭活酶引起的抗生素抗性;(4)可移动的细菌遗传耐药基因元件及其转移与抗生素抗性.本文基于以上几个方面综述了与沙门氏菌抗生素抗性机理研究相关的研究动态和研究进展.     

裂解酶治疗的研究进展与应用前景

多耐药病原细菌的不断出现和传播给公共医疗造成了严峻的威胁和挑战,开发新的抗菌分子迫在眉睫。噬菌体裂解酶来源于噬菌体,具有独特的进化和选择优势,不仅能高效快速的杀灭多耐药细菌,而且不易诱导细菌产生新的耐药性。本文对噬菌体裂解酶的结构和功能进行了简要的介绍,重点综述了裂解酶在抗细菌感染中近年的研究进展和应用前景。     

新生儿医院感染产超广谱β-内酰胺酶细菌流行状况及耐药性分析

目的了解新生儿医院感染中产超广谱β-内酰胺酶（ESBLs）细菌流行状况及耐药性,为预防和控制感染提供依据。方法对2011年1月至2013年12月间新生儿医院感染病原菌分布及耐药性进行回顾性分析;用VITEK-2 Compact微生物鉴定系统鉴定菌种和药敏试验。结果共检出病原菌192株,105株为肺炎克雷伯菌和大肠埃希菌,占54.7%;检出产ESBLs菌58株,全部来自肺炎克雷伯菌和大肠埃希菌;产ESBLs菌对青霉素类、头孢菌素类、单内酰环类抗菌药物高度耐药,耐药率〉80.0%,对头孢哌酮/舒巴坦、哌拉西林/他唑巴坦耐药率较低,耐药率〈20.0%,未检测到亚胺培南和美罗培南耐药株。结论产ESBLs肺炎克雷伯菌和大肠埃希菌是新生儿医院感染中主要的病原菌,且对常用抗菌药物耐药率较高,临床应加强病原菌的耐药性监测,合理使用抗菌药物。     

致病性葡萄球菌cfr基因介导的多重耐药机制研究进展

葡萄球菌是临床常见致病菌及食源性致病菌,可在食品原料加工、包装及运输过程中污染食品,引起人体多种严重感染,其耐药性的不断增强对公共卫生安全产生了重大的威胁。葡萄球菌中cfr (chloramphenicol-florfenicol resistance)基因编码的甲基转移酶,可引起细菌核糖体RNA的甲基化,从而阻碍或减弱多种化学结构不同的抗生素与肽基转移酶活性中心(peptidyl transferase center,PTC)的结合,导致葡萄球菌多重耐药表型的出现。噁唑烷酮类药物−利奈唑胺是继万古霉素后治疗耐药革兰氏阳性菌所致感染的最后一道防线,cfr基因的出现大大加速了利奈唑胺耐药性的传播。cfr基因广泛分布于多种致病性葡萄球菌中,cfr基因与各类型可转移元件(质粒、转座子和整合相关元件等)密切关联的遗传环境是其广泛传播的结构基础。在cfr基因水平传播的过程中,食源性致病葡萄球菌作为中间者扮演着重要的角色。本文就近年来国内外对致病性葡萄球菌中cfr基因的分布状况、耐药机制、遗传环境、传播机制等进行综述,以期为防控致病性葡萄球菌的传播提供参考,以遏制多重耐药菌的进一步传播。     

Antibiotics and anaerobes of gut origin

Hundreds of bacterial species make up human gut flora. Of these, 99% are anaerobic bacteria. Although anaerobes are part of the normal commensal flora, they can become opportunistic pathogens, causing serious, sometimes fatal infections if they escape from the colonic milieu. Most often, this escape occurs as a result of perforation, surgery, diverticulitis or cancer. Infections involving anaerobic bacteria are often difficult to treat because antibiotic resistance is increasing among the genera, mediated primarily through horizontal transfer of a plethora of mobile DNA transfer factors. Some of these transfer factors can also be transmitted to aerobic bacteria. It is becoming increasingly clear that antibiotic resistance trends have to be carefully monitored, and the transfer factors and mechanisms of transfer understood at a molecular level to avoid negative clinical outcomes when infections involve anaerobic bacteria.     

Resistance acquisition via the bacterial SOS response: the inducive role of antibiotics

After the euphoria of the antibiotic discovery and their tremendous action on bacterial infections outcomes, arrives a period of fear with the continuous emergence of bacteria that are resistant to almost all antibiotic treatments. It is becoming essential to better understand antibiotic resistance mechanisms to find new approaches to prevent the worldwide problem of multiresistance. The role of antibiotics on the direct induction of resistance acquisition is known. Recent studies have shown that some antibiotics, by inducing the bacterial SOS response, global repair response after DNA damages, are involved on a broader level in the induction, acquisition and dissemination of resistances in bacteria. We discuss here the role of antibiotics in resistance acquisition via the SOS response through several examples and the interest of identifying the SOS response regulators as the future targets of new families of antimicrobial molecules.     

Emerging High-Level Tigecycline Resistance: Novel Tetracycline Destructases Spread via the Mobile Tet(X)

Antibiotic resistance in bacteria has become a great threat to global public health. Tigecycline is a next-generation tetracycline that is the final line of defense against severe infections by pan-drug-resistant bacterial pathogens. Unfortunately, this last-resort antibiotic has been challenged by the recent emergence of the mobile Tet(X) orthologs that can confer high-level tigecycline resistance. As it is reviewed here, these novel tetracycline destructases represent a growing threat to the next-generation tetracyclines, and a basic framework for understanding the molecular epidemiology and resistance mechanisms of them is presented. However, further large-scale epidemiological and functional studies are urgently needed to better understand the prevalence and dissemination of these newly discovered Tet(X) orthologs among Gram-negative bacteria in both human and veterinary medicine.     

Do we need an intravenous fluoroquinolone?

Intravenous ciprofloxacin, the first parenteral fluoroquinolone available in this country, represents another class of antimicrobial agents from which physicians must choose when treating nosocomial infections. Fluoroquinolones are bactericidal antimicrobial agents that act by inhibiting DNA gyrase. They are active in vitro against most gram-negative bacteria and methicillin-susceptible staphylococci. Activity against anaerobic bacteria and streptococci is poor. The rapid development of bacterial resistance in centers with high quinolone usage is of great concern. Resistance develops most commonly in Pseudomonas aeruginosa and staphylococci. Resistance emerges most often when quinolones are used to treat chronic infections or in patients with poorly drained abscesses, necrotic tissue, or indwelling catheters. Clinical trials have shown ciprofloxacin to be as effective as ceftazidime in the treatment of infections caused by gram-negative bacteria. Although the overall frequency of side effects to fluoroquinolones is low, seizures and allergic reactions have been attributed to their use. Ciprofloxacin inhibits the metabolism of theophylline, and morbidity and death have been reported in patients taking the two drugs concomitantly. Parenteral fluoroquinolones should be reserved for the treatment of gram-negative bacterial infections in patients in whom standard agents cannot be used.     

Insects Represent a Link between Food Animal Farms and the Urban Environment for Antibiotic Resistance Traits

Antibiotic-resistant bacterial infections result in higher patient mortality rates, prolonged hospitalizations, and increased health care costs. Extensive use of antibiotics as growth promoters in the animal industry represents great pressure for evolution and selection of antibiotic-resistant bacteria on farms. Despite growing evidence showing that antibiotic use and bacterial resistance in food animals correlate with resistance in human pathogens, the proof for direct transmission of antibiotic resistance is difficult to provide. In this review, we make a case that insects commonly associated with food animals likely represent a direct and important link between animal farms and urban communities for antibiotic resistance traits. Houseflies and cockroaches have been shown to carry multidrug-resistant clonal lineages of bacteria identical to those found in animal manure. Furthermore, several studies have demonstrated proliferation of bacteria and horizontal transfer of resistance genes in the insect digestive tract as well as transmission of resistant bacteria by insects to new substrates. We propose that insect management should be an integral part of pre- and postharvest food safety strategies to minimize spread of zoonotic pathogens and antibiotic resistance traits from animal farms. Furthermore, the insect link between the agricultural and urban environment presents an additional argument for adopting prudent use of antibiotics in the food animal industry.     

Large-scale screening of a targeted Enterococcus faecalis mutant library identifies envelope fitness factors

Spread of antibiotic resistance among bacteria responsible for nosocomial and community-acquired infections urges for novel therapeutic or prophylactic targets and for innovative pathogen-specific antibacterial compounds. Major challenges are posed by opportunistic pathogens belonging to the low GC% gram-positive bacteria. Among those, Enterococcus faecalis is a leading cause of hospital-acquired infections associated with life-threatening issues and increased hospital costs. To better understand the molecular properties of enterococci that may be required for virulence, and that may explain the emergence of these bacteria in nosocomial infections, we performed the first large-scale functional analysis of E. faecalis V583, the first vancomycin-resistant isolate from a human bloodstream infection. E. faecalis V583 is within the high-risk clonal complex 2 group, which comprises mostly isolates derived from hospital infections worldwide. We conducted broad-range screenings of candidate genes likely involved in host adaptation (e.g., colonization and/or virulence). For this purpose, a library was constructed of targeted insertion mutations in 177 genes encoding putative surface or stress-response factors. Individual mutants were subsequently tested for their i) resistance to oxidative stress, ii) antibiotic resistance, iii) resistance to opsonophagocytosis, iv) adherence to the human colon carcinoma Caco-2 epithelial cells and v) virulence in a surrogate insect model. Our results identified a number of factors that are involved in the interaction between enterococci and their host environments. Their predicted functions highlight the importance of cell envelope glycopolymers in E. faecalis host adaptation. This study provides a valuable genetic database for understanding the steps leading E. faecalis to opportunistic virulence.     

Comparative genomics of multidrug resistance in Acinetobacter baumannii

Acinetobacter baumannii is a species of nonfermentative gram-negative bacteria commonly found in water and soil. This organism was susceptible to most antibiotics in the 1970s. It has now become a major cause of hospital-acquired infections worldwide due to its remarkable propensity to rapidly acquire resistance determinants to a wide range of antibacterial agents. Here we use a comparative genomic approach to identify the complete repertoire of resistance genes exhibited by the multidrug-resistant A. baumannii strain AYE, which is epidemic in France, as well as to investigate the mechanisms of their acquisition by comparison with the fully susceptible A. baumannii strain SDF, which is associated with human body lice. The assembly of the whole shotgun genome sequences of the strains AYE and SDF gave an estimated size of 3.9 and 3.2 Mb, respectively. A. baumannii strain AYE exhibits an 86-kb genomic region termed a resistance island—the largest identified to date—in which 45 resistance genes are clustered. At the homologous location, the SDF strain exhibits a 20 kb-genomic island flanked by transposases but devoid of resistance markers. Such a switching genomic structure might be a hotspot that could explain the rapid acquisition of resistance markers under antimicrobial pressure. Sequence similarity and phylogenetic analyses confirm that most of the resistance genes found in the A. baumannii strain AYE have been recently acquired from bacteria of the genera Pseudomonas, Salmonella, or Escherichia. This study also resulted in the discovery of 19 new putative resistance genes. Whole-genome sequencing appears to be a fast and efficient approach to the exhaustive identification of resistance genes in epidemic infectious agents of clinical significance.     

The horizontal flow of the plasmid resistome: clues from inter‐generic similarity networks

By integrating sequence similarity data of plasmid‐encoded antibiotic resistance determinants with those coming from a less transferred molecular marker, we constructed a network in which all the sequences that most likely underwent horizontal gene transfer (HGT) were linked together. The analysis of this network revealed that either geographical barriers or taxonomical distance can often be overcome since phylogenetically unrelated bacteria, and/or those inhabiting distinct environments, were found to share common antibiotic resistance determinants, probably as a result of (one or multiple) HGT event(s). Data obtained also revealed that bacteria viable through multiple environments (ubiquitous) are likely to give a crucial contribution to the spreading of bacterial resistance towards antimicrobial compounds. These analyses represent a first attempt to give an almost global picture of the horizontal flow of antibiotic resistance determinants at the whole bacterial community level, also underlining the power of HGT among bacteria and how this ‘horizontal flow’ is poorly affected by both taxonomy and physical distance. Finally, data presented may be useful in the infections control procedures, suggesting which bacterial species are more likely acting as vectors of antibiotic resistance determinants.     

水环境中耐药菌污染与危害研究进展

细菌在抗菌药选择性压力下产生耐药性并可传代,通过质粒和整合子等可移动基因元件将耐药基因在相同或不同种属中广泛传播,导致细菌多重耐药,并可通过多种途径进入水体,水环境日益成为庞大的耐药基因库,为致病菌及条件致病菌提供获得大量耐药基因的机会,若多重耐药菌再次侵入人体,可能引发严重的公共卫生问题。     

Exploring the role of the immune response in preventing antibiotic resistance

For many bacterial infections, drug resistant mutants are likely present by the time antibiotic treatment starts. Nevertheless, such infections are often successfully cleared. It is commonly assumed that this is due to the combined action of drug and immune response, the latter facilitating clearance of the resistant population. However, most studies of drug resistance emergence during antibiotic treatment focus almost exclusively on the dynamics of bacteria and the drug and neglect the contribution of immune defenses. Here, we develop and analyze several mathematical models that explicitly include an immune response. We consider different types of immune responses and investigate how each impacts the emergence of resistance. We show that an immune response that retains its strength despite a strong drug-induced decline of bacteria numbers considerably reduces the emergence of resistance, narrows the mutant selection window, and mitigates the effects of non-adherence to treatment. Additionally, we show that compared to an immune response that kills bacteria at a constant rate, one that trades reduced killing at high bacterial load for increased killing at low bacterial load is sometimes preferable. We discuss the predictions and hypotheses derived from this study and how they can be tested experimentally.     

Soil microbial communities drive the resistance of ecosystem multifunctionality to global change in drylands across the globe

The relationship between soil microbial communities and the resistance of multiple ecosystem functions linked to C, N and P cycling (multifunctionality resistance) to global change has never been assessed globally in natural ecosystems. We collected soils from 59 dryland ecosystems worldwide to investigate the importance of microbial communities as predictor of multifunctionality resistance to climate change and nitrogen fertilisation. Multifunctionality had a lower resistance to wetting–drying cycles than to warming or N deposition. Multifunctionality resistance was regulated by changes in microbial composition (relative abundance of phylotypes) but not by richness, total abundance of fungi and bacteria or the fungal: bacterial ratio. Our results suggest that positive effects of particular microbial taxa on multifunctionality resistance could potentially be controlled by altering soil pH. Together, our work demonstrates strong links between microbial community composition and multifunctionality resistance in dryland soils from six continents, and provides insights into the importance of microbial community composition for buffering effects of global change in drylands worldwide.     

Bactericidal,quorum quenching and anti-biofilm nanofactories: a new niche for nanotechnologists

Despite several conventional potent antibacterial therapies, bacterial infections pose a significant threat to human health because they are emerging as the leading cause of death worldwide. Due to the development of antibiotic resistance in bacteria, there is a pressing demand to discover novel approaches for developing more effective therapies to treat multidrug-resistant bacterial strains and biofilm-associated infections. Therefore, attention has been especially devoted to a new and emerging branch of science “nanotechnology” to design non-conventional antimicrobial chemotherapies. A range of nanomaterials and nano-sized carriers for conventional antimicrobial agents have fully justified their potential to combat bacterial diseases by reducing cell viability, by attenuating quorum sensing, and by inhibiting/or eradicating biofilms. This communication summarizes emerging nano-antimicrobial therapies in treating bacterial infections, particularly using antibacterial, quorum quenching, and anti-biofilm nanomaterials as new approaches to tackle the current challenges in combating infectious diseases.     

Alarming β-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae

Resistance to β-lactams and other antibiotics in the Enterobacteriaceae is frequently associated with plasmidic resistance determinants that are easily transferred among species. β-Lactamase-mediated resistance is increasingly associated with plasmid-encoded extended-spectrum β-lactamases (ESBLs) and carbapenemases, specifically the CTX-M family of ESBLs, the KPC family of serine carbapenemases, and the VIM, IMP, and NDM-1 metallo-β-lactamases. Although clonal dispersion of resistant isolates was seen initially, more diverse genetic platforms are being observed as variations of mobile elements are transferred worldwide. These enzymes are now appearing in multiple combinations of ESBLs and carbapenemases, thereby conferring resistance to virtually all β-lactam antibiotics.     

呼吸机相关性肺炎的常见病原菌耐药性分析

目的:探讨呼吸机相关性肺炎(VAP)的常见病原菌并分析其耐药性,为临床治疗提供依据。方法:选取我院收治的135例VAP患者的临床资料,分析其病原菌分布以及抗菌药物的耐药性。结果:135例患者中共分离出183株病原菌,其中革兰氏阴性菌135株(占73.77%),革兰氏阳性细菌33株(占18.03%),真菌15株(占8.20%)。革兰氏阴性菌主要为鲍曼不动杆菌,占35.52%,革兰氏阳性细菌主要为金黄色葡萄球菌,占9.84%,革兰阳性菌无一对万古霉素耐药,除了米诺环素总耐药率为42.42%外,其余病原菌对于常用的药物总耐药率均大于60.0%,革兰阴性菌普遍存在多药耐药现象。结论:引起VAP患者感染的主要致病菌为革兰阴性菌群,且存在严重的多重耐药现象,在临床上应加强对VAP疾病的预防和控制,合理应用抗菌药物。     

Origin, evolution, and migration of drug resistance genes

Current views on the mechanisms responsible for the emergence of multiple drug resistance in clinical bacterial isolates are considered. Hypotheses on the origin of resistance genes derived from determinants of actinomycetes, antibiotic producers, and chromosomal genes of bacteria involved in cellular metabolism are reviewed. The mechanisms underlying the diffusion of resistance determinants by means of bacterial mobile elements (plasmids, transposons, and integrons) are discussed. Examples of the horizontal transfer of resistance determinants between Gram-positive and Gram-negative bacteria are presented.