Clinical pharmacology of antimicrobial use in humans and animals

Veterinary public health is a frontier in the fight against human disease, charged to control and eradicate zoonotic diseases that are naturally transmitted between vertebrate animals and man. Currently there is a need for clinical pharmacologists and all health care givers to limit the development of bacterial resistance in humans to contain the increased health care expenditures related to morbidity and mortality associated with the use of antimicrobials. The development of resistance predates the use of antibiotics and will always be a problem to the successful treatment of patients. Ongoing discussion debates the extent to which antibiotic use in animals contributes to the development of antibiotic resistance in humans. The veterinary use ofantibiotics as antimicrobial growth promoters is thought to influence the prevalence of resistance in animal bacteria and to be a risk factor for the emergence of antibiotic resistance in human pathogens. Transfer of antibiotic resistant bacteria from animals to humans may occur via contact, including occupational exposure and via the food chain. Resistance genes may transferfrom bacteria of animals to human pathogens in the intestinal flora of humans. Prevention of the development of resistance in humans necessitates good animal husbandry and hygienic measures to prevent cross contamination and a decrease in the use of antibiotics. Appropriate use of antibiotics for food animals will preserve the long-term efficacy of existing antibiotics, support animal health and welfare, and limit the risk of transfer of antibiotic resistance to humans. Investigators must also develop new antimicrobial agents. Poole (J Pharmacy Pharmacol 2001;53:283) recommends targeting the three predominate mechanisms of development of resistance by antimicrobials (i.e., antibiotic inactivation, target site modification, and altered uptake via restricted entry and/or enhanced efflux) to specifically complement the development of novel agents with novel bacterial targets. Bacterial resistance and its selection may be evaluated by comparing the relationship to antibiotic pharmacokinetic (PK) values obtained from serum concentrations and organism MICs (minimum inhibitory concentrations; concentration-dependent killing) to reveal culture and sensitivity tests in patients. Pharmacodynamic (PD) models may be developed to identify factors associated with the probability that bacterial resistance will develop. Thomas et al (Antimicrobial Agents Chemotherapy 1998;42:521) used this combined approach of PK/PD and MICs to examine data retrospectively. The role of clinical pharmacology is to work with PK/PD models such as these to determine the best use of antibiotics in humans to minimize the development of resistance. The role of any regulatory body responsible for the protection of the public health and food safety for consumers is to assess risk and to then communicate and manage the risk. Scientific uncertainty must be interpreted to propose sound policy options. The conversion of sound science into an appropriate regulatory policy to protect the public health is most important.     

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.     

Comparing the selective and co-selective effects of different antimicrobials in bacterial communities

Bacterial communities are exposed to a cocktail of antimicrobial agents, including antibiotics, heavy metals and biocidal antimicrobials such as quaternary ammonium compounds (QACs). The extent to which these compounds may select or co-select for antimicrobial resistance (AMR) is not fully understood. In this study, human-associated, wastewater-derived bacterial communities were exposed to either benzalkonium chloride (BAC), ciprofloxacin or trimethoprim at sub-point-of-use concentrations for one week to determine selective and co-selective potential. Metagenome analyses were performed to determine effects on bacterial community structure and prevalence of antibiotic resistance genes (ARGs) and metal or biocide resistance genes (MBRGS). Ciprofloxacin had the greatest co-selective potential, significantly enriching for resistance mechanisms to multiple antibiotic classes. Conversely, BAC exposure significantly reduced relative abundance of ARGs and MBRGS, including the well characterised qac efflux genes. However, BAC exposure significantly impacted bacterial community structure. Therefore BAC, and potentially other QACs, did not play as significant a role in co-selection for AMR as antibiotics such as ciprofloxacin at sub-point-of-use concentrations in this study. This approach can be used to identify priority compounds for further study, to better understand evolution of AMR in bacterial communities exposed to sub-point-of-use concentrations of antimicrobials.     

某院2009～2011年细菌耐药率变化与抗菌药物使用量关系的研究

目的了解2009年1月～2011年12月笔者所在医院医院感染常见病原菌的耐药变化趋势及抗菌药物使用量,探讨抗菌药物使用量与病原菌耐药率之间的相关性。方法对3年间13种抗菌药物使用量与医院感染常见病原菌对目标抗菌药物耐药率进行统计分析,计算各药的用药频度,对耐药率与DDDs进行相关性分析。结果 3年期间病原菌耐药率逐步上升,期间笔者所在医院有9种抗菌药物DDDs的变化与治疗目标菌的耐药率变迁呈显著相关。结论抗菌药物的广泛使用或使用不当与加速细菌耐药的产生和发展可能有着密切联系,规范抗菌药物的使用对延缓细菌耐药性的发展有着重要意义。     

Mobile genes coding for efflux-mediated antimicrobial resistance in Gram-positive and Gram-negative bacteria

Efflux mechanisms that account for resistance to a variety of antimicrobial agents are commonly found in a wide range of bacteria. Two major groups of efflux systems are known, specific exporters and transporters conferring multidrug resistance (MDR). The MDR systems are able to remove antimicrobials of different classes from the bacterial cell and occasionally play a role in the intrinsic resistance of some bacteria to certain antimicrobials. Their genes are commonly located on the bacterial chromosome. In contrast, the genes coding for specific efflux systems are often associated with mobile genetic elements which can easily be interchanged between bacteria. Specific efflux systems have mainly been identified with resistances to macrolides, lincosamides and/or streptogramins, tetracyclines, as well as chloramphenicol/florfenicol in Gram-positive and Gram-negative bacteria. In this review, we focus on the molecular biology of antimicrobial resistance mediated by specific efflux systems and highlight the association of the respective resistance genes with mobile genetic elements and their distribution across species and genus borders.     

Bacterial resistance to antibiotics: modified target sites

Alteration in the target sites of antibiotics is a common mechanism of resistance. Examples of clinical strains showing resistance can be found for every class of antibiotic, regardless of the mechanism of action. Target site changes often result from spontaneous mutation of a bacterial gene on the chromosome and selection in the presence of the antibiotic. Examples include mutations in RNA polymerase and DNA gyrase, resulting in resistance to the rifamycins and quinolones, respectively. In other cases, acquisition of resistance may involve transfer of resistance genes from other organisms by some form of genetic exchange (conjugation, transduction, or transformation). Examples of these mechanisms include acquisition of the mecA genes encoding methicillin resistance in Staphylococcus aureus and the various van genes in enterococci encoding resistance to glycopeptides.     

Mechanisms of antimicrobial resistance: their clinical relevance in the new millennium

Antimicrobials show selective toxicity. Suitable targets for antimicrobials to act at include the bacterial cell wall, bacterial protein and folic acid synthesis, nucleic acid metabolism in bacteria and the bacterial cell membrane. Acquired antimicrobial resistance generally can be ascribed to one of five mechanisms. These are production of drug-inactivating enzymes, modification of an existing target, acquisition of a target by-pass system, reduced cell permeability and drug removal from the cell. Introduction of a new antimicrobial into clinical practice is usually followed by the rapid emergence of resistant strains of bacteria in some species that were initially susceptible. This has reduced the long-term therapeutic value of many antimicrobials. It used to be thought that antibacterial resistance was mainly a hospital problem but now it is also a major problem in the community. Organisms in which resistance is a particular problem in the community include members of the Enterobacteriaceae, including Salmonella spp. and Shigella spp., Mycobacterium tuberculosis, Streptococcus pneumoniae, Haemophilus influenzae and Neisseria gonorrhoeae. Multi-resistant Gram-negative rods, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci are major causes of concern in the hospital setting. Prevalence of antibacterial resistance depends both on acquisition and spread. Decreasing inappropriate usage of antimicrobials should lessen the rate of acquisition, and spread can be minimised by sensible infection control measures.     

病原菌耐药性与抗菌药物消耗量相关性的研究进展

病原菌耐药性是指细菌使抗菌药物治疗作用下降的一种状态。耐药菌的出现使临床感染性疾病的治疗难度增加,抗菌药物的不合理使用是细菌耐药产生的主要原因,全国范围内或区域医疗机构内有效的抗菌药物管理策略,能够减少抗菌药物使用并逆转细菌耐药性的产生。国内外有关抗菌药物使用与病原菌耐药性相关性的研究较多,国内缺少对全国性或区域性的研究数据。通过综述近年来国内外有关金黄色葡萄球菌、粪肠球菌、屎肠球菌、大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、鲍曼不动杆菌、阴沟肠杆菌及其他病原菌的耐药性与常用抗菌药物消耗量的相关性,从宏观数据上把握两者间的关系,以期为医院感染的管理提供证据支持。     

Co-resistance: an opportunity for the bacteria and resistance genes

Co-resistance involves transfer of several genes into the same bacteria and/or the acquisition of mutations in different genetic loci affecting different antimicrobials whereas pleiotropic resistance implies the same genetic event affecting several antimicrobials. There is an increasing prevalence of isolates with co-resistance which are over-represented within the so-called high-risk clones. Compensatory events avoid fitness cost of co-resistance, even in the absence of antimicrobials. Nevertheless, they might be selected by different antimicrobials and a single agent might select co-resistant isolates. This process, named as co-selection, is not avoided with cycling or mixing strategies of antimicrobial use. Co-resistance and co-selection processes increase the opportunity for persistence of the bacteria and resistance genes and should be considered when designing strategies for decreasing antimicrobial resistance.     

Inhibiting conjugation as a tool in the fight against antibiotic resistance

Antibiotic resistance, especially in gram-negative bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid-encoded conjugation system and the host-encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addition to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics.     

Mechanisms of quinolone resistance in Escherichia coli and Salmonella: recent developments

Fluoroquinolones are broad-spectrum antimicrobials highly effective for treatment of a variety of clinical and veterinary infections. Their antibacterial activity is due to inhibition of DNA replication. Usually resistance arises spontaneously due to point mutations that result in amino acid substitutions within the topoisomerase subunits GyrA, GyrB, ParC or ParE, decreased expression of outer membrane porins, or overexpression of multidrug efflux pumps. In addition, the recent discovery of plasmid-mediated quinolone resistance could result in horizontal transfer of fluoroquinolone resistance between strains. Acquisition of high-level resistance appears to be a multifactorial process. Care needs to taken to avoid overuse of this important class of antimicrobial in both human and veterinary medicine to prevent an increase in the occurrence of resistant zoonotic and non-zoonotic bacterial pathogens that could subsequently cause human or animal infections.     

我院2008年临床常见病原菌耐药性分析

目的:分析我院主要病原菌对抗菌药物的耐药性,为临床合理应用抗菌药物提供参考。方法:对2008年我院临床分离病原菌的耐药性进行回顾性分析。结果:临床分离的938株病原菌中,大肠埃希菌、金黄色葡萄球菌、肠杆菌属、表皮葡萄球菌、铜绿假单胞菌、克雷伯杆菌、不动杆菌、肠球菌、溶血性链球菌及变形杆菌位于前10位,为我院常见致病菌。结论:临床医师应合理选用抗菌药物,减少细菌耐药。     

细菌耐药耐受性机制的最新研究进展

抗生素的发现是人类抗感染史上伟大的里程碑。但是由于近年来人们对抗生素使用的认知不足,导致了抗生素滥用情况严重。抗生素耐药性以惊人的速度出现,现在已成为人类健康的主要威胁。由于抗生素的滥用导致了许多耐药细菌的产生,甚至出现了多重耐药细菌或者全耐药超级细菌。目前对于耐药细菌产生机制的研究进展已经比较成熟,近期研究发现细菌暴露在抗生素下会先变得耐受,耐受产生后会促进耐药性的产生。为有效尽早遏制耐药,有必要对于抗生素耐受的机制进行探究。目前关于细菌对抗生素耐受性产生的机制尚不完全清楚,本文主要介绍关于细菌对抗生素耐受性的研究进展,有利于加强人们对于耐受性细菌的认识,帮助预防、克服耐药。     

养殖业抗生素的使用及其潜在危害

细菌耐药性和食品安全问题业已引起全球的普遍关注。越来越多的证据表明,畜牧养殖业滥用抗生素对于细菌耐药性的出现和耐药基因的传播起着重要作用。了解养殖业抗生素的使用现状和滥用抗生素对人类健康的潜在危害,对我国限制及禁止畜牧养殖业抗生素的使用具有重要作用。     

The use of quorum-sensing blockers as therapeutic agents for the control of biofilm-associated infections

The development of novel antimicrobial compounds is required to treat the growing number of infections where antibiotic resistance is a serious threat, especially in situations where biofilms are involved. Antibiotic resistance is the result of two factors: first, through the development of specific antibiotic resistance, due to either mutation or the acquisition of antibiotic resistance genes; and second, by the innate tolerance of bacterial biofilms. Bacterial control, through the inhibition of bacterial cell-cell communication systems which are involved in the regulation of virulence factor production, host colonization, and biofilm formation, is discussed in this review. Specifically, this review presents current studies on the development of quorum-sensing inhibitors for the control of bacterial infections.     

DNase I induced DNA degradation is inhibited by neomycin

Preparations of antimicrobials from biotechnological sources containing nucleic acids may serve as vector for the dissemination of resistance genes. An essential prerequisite for the acquisition of a new resistance phenotype in a transformational scenario is the availability of physically intact DNA molecules capable of transforming competent microorganisms. DNA is thought to be an easy target for catabolic processes when present in the natural habitat of bacteria (e.g. gastrointestinal tract, soil) due to the overall presence of nucleolytic enzymes. Aminoglycoside antibiotics are known to display a strong affinity to nucleic acids rendering these compounds to be primary candidates for exerting DNA protective functions in the gastrointestinal tract when applied orally during antibiotic chemotherapy. Using a DNase I protection assay it could be demonstrated that neomycin B at a concentration of 2 mM completely inhibited degradation of plasmid DNA in vitro. No inhibition of degradation was observed with streptomycin and kanamycin and the non-aminoglycoside antibiotics oxytetracycline and ampicillin under identical assay conditions. Thus, neomycin preparations may be able to promote structural integrity of contaminating DNA-fragments in DNase-rich environments.     

兽用抗菌药耐药判定标准的研究进展

兽用抗菌药因其可以有效地预防和治疗动物疾病而被广泛使用，造成了严重的细菌耐药。目前，兽药抗菌药的耐药判定主要参考美国临床和实验室标准协会(CLSI)和欧盟药敏试验标准委员会(EUCAST)公布的标准，但数据并不完整。我国近些年也开始建立适合自己国情的兽用抗菌药的耐药判定标准，但成果并不多。因此，急需建立和完善兽用抗菌药的耐药判定标准，以便于监测兽用抗菌药耐药性和指导临床准确使用兽用抗菌药。本文主要综述了CLSI和EUCAST两大组织已经公布的部分兽用抗菌药的耐药判定标准，以及近年来国内外兽用抗菌药耐药判定标准的研究进展，以期为兽用抗菌药耐药判定标准的发展提供理论参考。     

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%.     

Horizontal gene transfer—emerging multidrug resistance in hospital bacteria

The frequency and spectrum of antibiotic resistant infections have increased worldwide during the past few decades. This increase has been attributed to a combination of microbial characteristics, the selective pressure of antimicrobial use, and social and technical changes that enhance the transmission of resistant organisms. The resistance is acquired by mutational change or by the acquisition of resistance-encoding genetic material which is transfered from another bacteria. The spread of antibiotic resistance genes may be causally related to the overuse of antibiotics in human health care and in animal feeds, increased use of invasive devices and procedures, a greater number of susceptible hosts, and lapses in infection control practices leading to increased transmission of resistant organisms. The resistance gene sequences are integrated by recombination into several classes of naturally occurring gene expression cassettes and disseminated within the microbial population by horizontal gene transfer