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翻译：周超群
审核：陈志锦
更好地了解耐药细菌的起源和传播，以及鉴定新的抗微生物化合物和新型药物组合，将有助于开发更好的给药方案和新颖的策略来管理耐药性和防止耐药细菌的传播。
自从世卫组织和欧盟在2011年颁布了抗菌药物战略和行动计划以来，出现了前所未有的研究，旨在解决抗菌药物耐药危机，特别是抗菌药物（抗生素）。其中大部分重点在于更好地了解内在的、获得的和演变的等耐药的各个方面。这种了解是为了确保下一代新型、安全有效的抗生素具有临床使用寿命，并且不太容易发展成耐药性。
【耐药病原体的起源与传播】
了解耐药病原体出现的原因，以便能实施感染控制措施以防止其扩散。耐药菌的基因组流行病学揭示了某些耐药菌的全球传播和特定耐药基因的“热点”地区。这些信息可用于针对干预措施以防止进一步传播，例如获得清洁水、减少抗生素对环境的污染。 然而，一些耐药基因，如超广谱β-内酰胺酶（ESBLs）的耐药基因现在已遍布全球，并且在没有症状感染的情况下可以持续在健康个体和动物的肠道微生物群中存活数月。 研究如何根除细菌中的这种耐药基因或鼓励“重塑”建立药物敏感细菌可以降低耐药流行率。
通常，临床相关的耐药性是通过编码源自环境微生物基因的遗传因素来赋予的，如Klyvera spp（blaCTX-M基因））和Shewanella spp（qnr基因）。对抗新药物的耐药机制似乎也是如此。数据质量和宏基因组研究的解释导致了在确定生命和栖息地各个领域的覆盖面的广度和深度方面取得了重大进展。所得到的功能性宏基因组数据库可用于确定环境微生物中是否存在对抗新药物的耐药性，并且应该与确定是否能够与从头阻止抗性同时进行。应该从宏基因组文库中找出可传播的耐药性，这种新药的许可证的要求可能包括确保其仅在世界上不产生耐药环境生物体的那些地区使用。
【耐药的监测和机制】
重要的是，必须了解耐药性的地理分布。这将使得战略上能够使用仍具有临床效果的药物，并减少新药物的引进，直到它们必须引进为止。持续的全球监测应提供对新药耐药性的早期鉴定，并作用于引进控制策略。在现行的情况下，全球监测往往仍然使用表型测试。这是因为基因技术及其诠释在低收入和中等收入国家尚未广泛应用。此外，可以鉴别的耐药基因和突变谱系尚不不完整。目前，这意味着完全依赖全基因组测序( WGS)数据的监测只能为已知的耐药基因提供有意义的信息。
WGS在确定特定耐药基因和细菌菌株(序列类型)的起源和传播方面起着至关重要的作用。当大数据集可用时，全基因组关联研究（GWAS）是确定实验室检测新耐药基因的有用工具。目前，WGS是对新药物细菌耐药性检测的“金标准”，有助于阐明新药的耐药机制，如唑来曲坦( etx0914)。
【耐药定量风险评估】
如果仅仅在某个国家分离的细菌菌株中首次描述了新的耐药性，并不意味着它在该国出现。此外，显示出动物出现耐药、动物耐药性传播给人类以及对人类抗生素治疗有害的影响等完整事件序列的证据仍难以明确。最有说服力的证据来自于人畜共患病原体，如弯曲杆菌属和沙门氏菌属的研究。研究应着重于从一个环境转移到另一个环境中的耐药性细菌的量化，并通过食物链有明确的动物来源证据在感染病原体个体中重点药物治疗失败进行定量分析。
虽然基因突变或传染性基因不能左右临床相关耐药性水平，但是这种菌株的生存优势可以促进其他突变的进化，这可能最终导致全面的临床耐药性。然而，耐药基因或基因突变的有效性并不一定意味着它将在群体中变得固定。诸如耐药性基因是否可以转移到其他细菌或细菌生长或感染宿主的能力等也是重要的因素。
【新抗菌药物的来源】
发现，研究和开发新型抗生素不再仅仅是大型制药公司的领域。通过生产性生物和创新化学进行分子生物学操作，在在土壤、环境样品、昆虫、青蛙和海洋微生物中持续发现抗菌化合物。许多化合物对革兰氏阳性细菌具有活性，但是许多描述这些发现的出版物并不提供数据显示它们是否可以从试管应用到临床。此外，一些对革兰氏阳性菌活跃的新药已经通过批准。世界卫生组织清单中的第1类细菌引起感染最需要新的治疗方法就是新型抗菌药物。因此，可以认为，发现研究应主要关注鲍曼不动杆菌和铜绿假单胞菌，以及碳青霉烯类耐药菌、产ESBL酶肠杆菌科菌，其次是第2类和第3类病原体。阻碍对抗固有耐药革兰氏阴性菌活性新药开发的最重要的科学因素是找不到可以进入细菌细胞而不被多药外排泵排出的化合物。计算分析提供了新的规律，可以帮助识别具有克服这种“渗透性”障碍能力的分子。通过合成在体外对多重耐药革兰氏阴性细菌有活性的半合成化合物来论证这些应用。
在短期内，药物的新组合最有可能达到更有效的感染治疗。 事实上，在过去十年，许多公司已经采用了这一策略，致使最近许可的药物是已知药物（或已知类型的修饰化合物）与酶（通常为β-内酰胺酶）抑制剂的组合产品。不幸的是，抗生素和重新使用的非抗生素的一些组合显示在体外有效，然而实际的药理学和/或药代动力学性质不理想，使得这种组合不太可能在临床上应用。例如，与抗生素组合的洛哌丁胺被广泛应用的希望就很小，因为它可引起便秘。评估临床上实用的联合治疗至关重要。欧盟抗艾滋病耐药联合规划倡议项目将有希望提供急需的新信息，使研究能够集中在最有可能提供有效治疗的组合上。
【了解如何使用抗生素】
抗生素的循环使用，是指药物在医院使用一段时间，然后使用不同类别的不同药物，在很大程度上被证明是行不通的。通常，这是因为多重耐药细菌的存在，它们表现出不同的耐药机制，其编码在单个可传播基因上。因此，某一种药物的停用对这种菌株的流行没有影响，而且以后抗生素的循环使用也不见有用，除非在没有耐药性出现和传播之前研发出全新的抗菌药物。
最近的一篇文章对抗生素治疗的持续时间提出了质疑。21世纪的医学应该是循证的，不幸的是，目前的许多抗生素治疗方案缺乏数据来支持。迫切需要研究来指出目前获得许可的和新的、药物的最佳给药方案，使常驻微生物群落保持不变，并减少耐药性的发展。然而，这应扩展到所有部门，因为抗生素的减少不仅会降低抗生素对人类、动物和环境的影响，还能最大限度地减少耐药菌的筛选、扩散和传播。
文献来源：Piddock L J V. Understanding drug resistance will improve the treatment of bacterial infections. NAT REV MICROBIOL, 2017, 15(11): 639~640.
参考文献
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2. Basarab, G. S. et al. Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases. Sci. Rep. 5, 11827 (2015).
3. Fisher, J. F. & Mobashery, S. Endless resistance. Endless antibiotics?Medchemcomm 7, 37–49 (2016).
4. Richter, M. F. et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545, 299–304 (2017).
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原文：
Understanding drug resistance will improve the treatment of bacterial infections
An improved understanding of the origins and spread of drug-resistant bacteria, as well as the identification of novel antimicrobial compounds and new drug combinations, will facilitate the development of better dosing regimens and novel strategies to manage drug resistance and prevent the dissemination of resistant bacteria.
Since the WHO and European Union issued antimicrobial strategies and action plans in 2011, there has been an unprecedented volume of research aimed at resolving the crisis of antimicrobial drug resistance, particularly to antibacterial drugs (antibiotics). Much of this has been focused on providing a better understanding of the various aspects of resistance (intrinsic, acquired and evolved). This understanding is required to ensure that the next generation of new, safe and effective antibiotics has clinical longevity and is less susceptible to the development of resistance.
Origin and spread of resistant pathogens
It is essential to understand where resistant pathogens emerge so that infection control measures can be put in place to prevent their spread. Genomic epidemiology of drug-resistant bacteria has revealed the global spread of certain drug-resistant bacteria and geographical ‘hotspots’ of specific resistance genes. Such information can be used to target interventions to prevent further spread, such as access to clean water and reduction in pollution of the environment by antibiotics. However, some resistance genes, such as those that encode extended-spectrum β-lactamases (ESBLs), are now endemic across the world and can persist in the gut microbiome of healthy individuals and animals for many months in the absence of symptomatic infection. Research investigating how to eradicate such resistance genes from bacteria or encourage the re‑establishment of drug-susceptible bacteria provides the potential to decrease the prevalence of resistance.
Often, clinically relevant drug resistance is conferred by transmissible genetic elements that encode genes that originated in environmental microorganisms, such as Klyvera spp (blaCTX‑M genes) and Shewanella spp (qnr genes). It seems probable that the same will be true for resistance mechanisms against new drugs. The quality of data and interpretation of metagenomic studies have led to substantial progress being made in identifying the breadth and depth of the resistome across all domains of life and habitats. The resulting functional metagenomic libraries could be used to determine whether resistance to a new drug is present in environmental microorganisms, and this should be done in parallel with determining whether de novo resistance can evolve. Should transmissible resistance be identified from metagenomic libraries, a requirement for the license of such a new drug could include ensuring that it is only used in those parts of the world in which the environmental organism does not occur.
Surveillance and mechanisms of resistance
It is essential that the geographical spread of drug resistance is known. This will enable the strategic use of drugs that remain clinically effective and reduce the introduction of new drugs until they are required. Continual global surveillance should provide early identification of resistance against a new drug and facilitate the introduction of control strategies. Where carried out, global surveillance often still uses phenotypic tests. This is because genomic technology and skilled interpretation is not widely available in low-income and middle-income countries. Furthermore, the repertoire of resistance genes and mutations that can be identified is incomplete. Currently, this means that surveillance that entirely relies on whole-genome sequencing (WGS) data can only provide meaningful information for known drug resistance genes.
WGS has been pivotal in identifying the origins and spread of specific resistance genes and bacterial strains (sequence types). When large datasets are available, genome-wide association studies (GWAS) are a useful tool to identify putative new resistance genes for laboratory experimentation. WGS of bacteria with evolved resistance to a new drug is now the ‘gold standard’ and has been helpful in elucidating the mechanism of resistance to new drugs, such as zoliflodacin (ETX0914).
Quantitative risk assessment of resistance
Just because new resistance is first described in a bacterial strain isolate in a certain country, it does not mean that it emerged in that country. Furthermore, evidence for the complete sequence of events that show the emergence of resistance in animals, spread to humans and deleterious effect on antibiotic treatment in people remains elusive. The most convincing evidence is provided from studies of zoonotic pathogens, such as Campylobacter spp. and Salmonella spp. Research should focus on quantifying the transfer of resistant bacteria from one environment to another and quantifying treatment failure of critically important drugs in individuals infected with pathogens for which there is unequivocal evidence of animal origin through the food chain.
Although mutation in a gene or a transmissible gene may not confer clinically relevant levels of drug resistance, the survival advantage of such strains can promote the evolution of additional mutations, which may eventually lead to full clinical drug resistance. However, the availability of a drug-resistance gene or gene mutation does not necessarily mean that it will become fixed in a population. Factors such as whether the resistance gene can be transferred to other bacteria or the ability of the bacterium to grow or infect the host are also important.
Sources of new antibacterial drugs
Discovery, research and development of new antibiotics are no longer the domain of large pharmaceutical companies. Antibacterial compounds continue to be discovered in soil, environmental samples, insects, frogs and marine microorganisms, through the molecular manipulation of producing organisms and innovative chemistry. Many compounds have activity for Grampositive bacteria, but numerous publications describing these findings do not provide data showing whether they could move from the test tube to the clinic. Furthermore, several new drugs that are active against Gram-positive bacteria have recently been approved. New treatments are most required for infections caused by bacteria in category 1 of the WHO list of bacteria for which new antibiotics are urgently required. Therefore, it could be argued that discovery research should primarily focus on carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant, ESBL-producing members of the Enterobacteriaceae, followed by pathogens in category 2 and category 3 . The most important scientific factor that hinders the development of new drugs that are active against intrinsically resistant Gram-negative bacteria is the failure to find compounds that can enter bacterial cells and are not pumped out by multidrug efflux pumps. Computational analysis has provided new rules that could help identify molecules with the ability to overcome this ‘permeability’ barrier. The application of these was demonstrated by the synthesis of a semi-synthetic compound that was active against multidrug-resistant Gram-negative bacteria in vitro.
In the short–medium term, new combinations of drugs are the most likely to lead to more effective treatments of infections. Indeed, in the past decade, many companies have adopted this strategy, which has led to the most recently licensed agents that are combination products of a known drug (or modified compound of a known class) with an enzyme (typically β-lactamase) inhibitor. Unfortunately, some of the combinations of antibiotic and a repurposed non-antibiotic shown to be effective in vitro have unfavourable pharmacological and/or pharmacokinetic properties; these make it unlikely that such combinations will be used in the clinic. For example, loperamide in combination with an antibiotic is unlikely to be widely used because it can cause constipation. It is essential that clinically practical combination treatments are evaluated. The projects by the European Union Joint Programming Initiative on Antimicrobial Resistance will hopefully provide much needed new information to enable research to focus on the combinations that are most likely to provide effective treatments.
Understanding how to use antibiotics
Cycling of antibiotics, whereby drugs are used for limited periods of times in hospitals and then a different drug of a different class is used, has largely proven unsuccessful.Typically, this has been because of the presence of multidrug-resistant bacteria, which exhibit different resistance mechanisms that are encoded on a single transmissible element. Therefore, withdrawal of one drug has no effect on the prevalence of such strains, and it is unlikely that cycling will be clinically useful in the future until there are entirely new drugs of novel classes to which no resistance has emerged and disseminated.
A recent article brought into question the duration of antibiotic treatment. Medicine in the 21st century should be evidence-based and unfortunately there is a dearth of data to support how to use many of the current antibiotic treatment regimens. Research is urgently required to indicate the best dosing schedules for currently licensed and new drugs so that the resident microbiota remains unchanged and the development of resistance is reduced. However, this should extend to all sectors, as a decrease in antibiotic use will not only reduce the effect of antibiotics on the human, animal and environmental microbiomes but also minimise the selection, proliferation and spread of drug-resistant bacteria.
图文编辑：王小虾
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发表于 2017-10-31 20:02:18