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Viral infections and pathogenesis of glaucoma: a comprehensive review. 青光眼的病毒感染及其发病机制综述。
IF 36.8 1区 医学 Q1 Medicine Pub Date : 2023-12-20 Epub Date: 2023-11-15 DOI: 10.1128/cmr.00057-23
Faraz Ahmad, Nikhil Deshmukh, Aaron Webel, Sandra Johnson, Ayman Suleiman, Rajiv R Mohan, Frederick Fraunfelder, Pawan Kumar Singh

Glaucoma is a leading cause of irreversible blindness worldwide, caused by the gradual degeneration of retinal ganglion cells and their axons. While glaucoma is primarily considered a genetic and age-related disease, some inflammatory conditions, such as uveitis and viral-induced anterior segment inflammation, cause secondary or uveitic glaucoma. Viruses are predominant ocular pathogens and can impose both acute and chronic pathological insults to the human eye. Many viruses, including herpes simplex virus, varicella-zoster virus, cytomegalovirus, rubella virus, dengue virus, chikungunya virus, Ebola virus, and, more recently, Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), have been associated with sequela of either primary or secondary glaucoma. Epidemiological and clinical studies suggest the association between these viruses and subsequent glaucoma development. Despite this, the ocular manifestation and sequela of viral infections are not well understood. In fact, the association of viruses with glaucoma is considered relatively uncommon in part due to underreporting and/or lack of long-term follow-up studies. In recent years, literature on the pathological spectrum of emerging viral infections, such as ZIKV and SARS-CoV-2, has strengthened this proposition and renewed research activity in this area. Clinical studies from endemic regions as well as laboratory and preclinical investigations demonstrate a strong link between an infectious trigger and development of glaucomatous pathology. In this article, we review the current understanding of the field with a particular focus on viruses and their association with the pathogenesis of glaucoma.

青光眼是世界范围内不可逆性失明的主要原因,由视网膜神经节细胞及其轴突的逐渐变性引起。虽然青光眼主要被认为是一种遗传性和年龄相关的疾病,但一些炎症性疾病,如葡萄膜炎和病毒引起的前段炎症,可引起继发性或葡萄膜性青光眼。病毒是主要的眼部病原体,可对人眼造成急性和慢性病理性损害。许多病毒,包括单纯疱疹病毒、水痘带状疱疹病毒、巨细胞病毒、风疹病毒、登革热病毒、基孔肯雅病毒、埃博拉病毒,以及最近的寨卡病毒(ZIKV)和严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2),都与原发性或继发性青光眼的后遗症有关。流行病学和临床研究表明,这些病毒与随后的青光眼发展之间存在关联。尽管如此,病毒感染的眼部表现和后遗症尚不清楚。事实上,病毒与青光眼的关联被认为相对罕见,部分原因是报告不足和/或缺乏长期随访研究。近年来,关于新发病毒感染病理谱的文献,如ZIKV和SARS-CoV-2,加强了这一主张,并更新了该领域的研究活动。来自流行地区的临床研究以及实验室和临床前调查表明,感染诱因与青光眼病理发展之间存在密切联系。在这篇文章中,我们回顾了目前对该领域的理解,特别关注病毒及其与青光眼发病机制的关系。
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引用次数: 0
Micro-nanoemulsion and nanoparticle-assisted drug delivery against drug-resistant tuberculosis: recent developments. 微纳米乳剂和纳米颗粒辅助给药治疗耐药结核病:最新进展。
IF 36.8 1区 医学 Q1 Medicine Pub Date : 2023-12-20 Epub Date: 2023-11-30 DOI: 10.1128/cmr.00088-23
Simpal Kumar Suman, Natarajan Chandrasekaran, C George Priya Doss

Tuberculosis (TB) is a major global health problem and the second most prevalent infectious killer after COVID-19. It is caused by Mycobacterium tuberculosis (Mtb) and has become increasingly challenging to treat due to drug resistance. The World Health Organization declared TB a global health emergency in 1993. Drug resistance in TB is driven by mutations in the bacterial genome that can be influenced by prolonged drug exposure and poor patient adherence. The development of drug-resistant forms of TB, such as multidrug resistant, extensively drug resistant, and totally drug resistant, poses significant therapeutic challenges. Researchers are exploring new drugs and novel drug delivery systems, such as nanotechnology-based therapies, to combat drug resistance. Nanodrug delivery offers targeted and precise drug delivery, improves treatment efficacy, and reduces adverse effects. Along with nanoscale drug delivery, a new generation of antibiotics with potent therapeutic efficacy, drug repurposing, and new treatment regimens (combinations) that can tackle the problem of drug resistance in a shorter duration could be promising therapies in clinical settings. However, the clinical translation of nanomedicines faces challenges such as safety, large-scale production, regulatory frameworks, and intellectual property issues. In this review, we present the current status, most recent findings, challenges, and limiting barriers to the use of emulsions and nanoparticles against drug-resistant TB.

结核病(TB)是一个主要的全球卫生问题,也是仅次于COVID-19的第二大流行传染病杀手。它是由结核分枝杆菌(Mtb)引起的,由于耐药,治疗变得越来越具有挑战性。1993年,世界卫生组织宣布结核病为全球卫生紧急事件。结核病的耐药性是由细菌基因组的突变驱动的,而这种突变可能受到长期药物暴露和患者依从性差的影响。耐药结核病的发展,如多重耐药、广泛耐药和完全耐药,构成了重大的治疗挑战。科学家们正在探索新的药物和新的药物输送系统,例如基于纳米技术的疗法,以对抗耐药性。纳米给药提供了靶向和精确的给药,提高了治疗效果,减少了不良反应。随着纳米级药物输送,具有有效治疗效果的新一代抗生素、药物再利用以及能够在较短时间内解决耐药性问题的新治疗方案(组合)可能是临床环境中有希望的治疗方法。然而,纳米药物的临床转化面临着诸如安全性、大规模生产、监管框架和知识产权问题等挑战。在这篇综述中,我们介绍了使用乳剂和纳米颗粒治疗耐药结核病的现状、最新发现、挑战和限制障碍。
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引用次数: 0
Experimental models for HIV latency and molecular tools for reservoir quantification-an update. HIV潜伏期的实验模型和储层定量的分子工具的更新。
IF 36.8 1区 医学 Q1 Medicine Pub Date : 2023-12-20 Epub Date: 2023-11-15 DOI: 10.1128/cmr.00013-23
Divyadarshini Angamuthu, Sandhya Vivekanandan, Luke Elizabeth Hanna

A major impediment for HIV cure is the ability of the virus to integrate its genome in the form of replication-competent proviral DNA into the cellular genome of the host and remain transcriptionally silent and hidden from the host's immune defense mechanisms in latent reservoir cells. These latent reservoirs are highly heterogeneous, long-lived cells that are capable of reactivating to restore the viremic stage in virally suppressed individuals upon treatment interruption, thus necessitating life-long antiretroviral treatment. Latency reversal has become one of the most explored therapeutic approaches for eliminating HIV reservoirs and effecting HIV cure. Various aspects governing the establishment, maintenance, and reversal of HIV latency continue to be an enigma and warrant further research. Quantifying the size of the latent reservoir pool is also a challenge as these cells are very few in number and cannot be easily differentiated from uninfected cells. This article provides a comprehensive review of the in vitro and in vivo models currently available for studying HIV latency as well as the recently developed molecular tools for detection and quantification of latent viral reservoirs.

HIV治愈的一个主要障碍是该病毒能够以具有复制能力的原病毒DNA的形式将其基因组整合到宿主的细胞基因组中,并在潜伏储存库细胞中保持转录沉默,不受宿主免疫防御机制的影响。这些潜伏的储存库是高度异质性的、长寿命的细胞,在治疗中断时能够在病毒抑制的个体中重新激活以恢复病毒血症阶段,因此需要终身抗逆转录病毒治疗。潜伏逆转已成为消除HIV病毒库和实现HIV治愈的研究热点之一。控制HIV潜伏期的建立、维持和逆转的各个方面仍然是一个谜,需要进一步的研究。由于这些细胞数量很少,并且不易与未感染的细胞区分,因此对潜伏库池的大小进行量化也是一项挑战。本文全面综述了目前用于研究HIV潜伏期的体外和体内模型,以及最近开发的用于检测和定量潜伏病毒库的分子工具。
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引用次数: 0
Wild-type distributions of minimum inhibitory concentrations and epidemiological cut-off values-laboratory and clinical utility. 最小抑制浓度和流行病学临界值的野生型分布-实验室和临床应用。
IF 36.8 1区 医学 Q1 Medicine Pub Date : 2023-12-20 Epub Date: 2023-12-01 DOI: 10.1128/cmr.00100-22
Gunnar Kahlmeter, John Turnidge

The characterization of wild-type minimum inhibitory concentration (MIC) and zone diameter distributions with the setting of epidemiological cut-off values (ECOFFs or ECVs) provides a reference for the otherwise relative MIC values in the international system for antimicrobial susceptibility testing. Distributions of MIC values for a species and an agent follow a log-normal distribution, which in the absence of resistance mechanisms is monomodal and designated wild type (WT). The upper end of the WT distribution, the ECOFF, can be identified with statistical methods. In the presence of phenotypically detectable resistance, the distribution has at least one more mode (the non-WT), but despite this, the WT is most often identifiable using the same methods. The ECOFF provides the most sensitive measure of resistance development in a species against an agent. The WT and non-WT modes are independent of the organism´s response to treatment, but when the European Committee on Antimicrobial Susceptibility Testing (EUCAST) determines the clinical breakpoints, the committee avoids breakpoints that split WT distributions of target species. This is to avoid the poorer reproducibility of susceptibility categorization when breakpoints split major populations but also because the EUCAST has failed to identify different clinical outcomes for isolates with different MIC values inside the wild-type distribution. In laboratory practice, the ECOFF is used to screen for and exclude resistance and allows the comparison of resistance between systems with different breakpoints from different breakpoint organizations, breakpoints evolving over time, and different breakpoints between human and animal medicine. The EUCAST actively encourages colleagues to question MIC distributions as presented on the website (https://www.eucast.org/mic_and_zone_distributions_and_ecoffs) and to contribute MIC and inhibition zone diameter data.

摘要通过设定流行病学临界值(ecoff或ECVs)对野生型最小抑菌浓度(MIC)和区径分布进行表征,为国际药敏试验体系中相对MIC值提供参考。一个物种和一种病原体的MIC值的分布遵循对数正态分布,在缺乏抗性机制的情况下,这种分布是单峰的,被称为野生型(WT)。WT分布的上端,即ECOFF,可以用统计方法识别。在存在表型可检测的抗性时,分布至少有一种模式(非WT),但尽管如此,WT通常使用相同的方法来识别。ECOFF提供了一个物种对一种药剂产生耐药性的最灵敏的测量方法。WT和非WT模式独立于生物体对治疗的反应,但当欧洲抗微生物药敏试验委员会(EUCAST)确定临床断点时,委员会避免了分裂目标物种WT分布的断点。这是为了避免当断点分裂主要种群时敏感性分类的可重复性较差,也是因为EUCAST未能识别野生型分布中具有不同MIC值的分离株的不同临床结果。在实验室实践中,ECOFF用于筛选和排除耐药性,并允许比较来自不同断点组织的具有不同断点的系统之间的耐药性,断点随着时间的推移而变化,以及人类和动物药物之间的不同断点。EUCAST积极鼓励同事们对网站(https://www.eucast.org/mic_and_zone_distributions_and_ecoffs)上的MIC分布提出质疑,并提供MIC和抑制带直径数据。
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引用次数: 0
Human strongyloidiasis: complexities and pathways forward. 人类强直性脊柱炎:复杂性和前进道路。
IF 19 1区 医学 Q1 MICROBIOLOGY Pub Date : 2023-12-20 Epub Date: 2023-11-08 DOI: 10.1128/cmr.00033-23
Dora Buonfrate, Richard S Bradbury, Matthew R Watts, Zeno Bisoffi

Strongyloidiasis is a World Health Organization neglected tropical disease usually caused by Strongyloides stercoralis, a parasitic worm with a complex life cycle. Globally, 300-600 million people are infected through contact with fecally contaminated soil. An autoinfective component of the life cycle can lead to chronic infection that may be asymptomatic or cause long-term symptoms, including malnourishment in children. Low larval output can limit the sensitivity of detection in stool, with serology being effective but less sensitive in immunocompromise. Host immunosuppression can trigger catastrophic, fatal hyperinfection/dissemination, where large numbers of larvae pierce the bowel wall and disseminate throughout the organs. Stable disease is effectively treated by single-dose ivermectin, with disease in immunocompromised patients treated with multiple doses. Strategies for management include raising awareness, clarifying zoonotic potential, the development and use of effective diagnostic tests for epidemiological studies and individual diagnosis, and the implementation of treatment programs with research into therapeutic alternatives and medication safety.

SUMMARYS圆线虫病是世界卫生组织忽视的一种热带疾病,通常由圆线虫引起,圆线虫是一种具有复杂生命周期的寄生虫。在全球范围内,有3亿至6亿人因接触被粪便污染的土壤而感染。生命周期中的自身感染成分可能导致无症状的慢性感染或导致长期症状,包括儿童营养不良。幼虫产量低会限制粪便检测的灵敏度,血清学有效,但对免疫功能低下的检测灵敏度较低。宿主免疫抑制可引发灾难性的、致命的过度感染/传播,大量幼虫刺穿肠壁并传播到整个器官。稳定的疾病可通过单剂量伊维菌素有效治疗,免疫功能低下患者可通过多剂量治疗。管理策略包括提高认识,阐明人畜共患的潜力,开发和使用有效的诊断测试进行流行病学研究和个人诊断,以及实施治疗方案,研究治疗替代方案和药物安全性。
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引用次数: 0
2023 Acknowledgment of CMR Reviewers. 2023 感谢 CMR 评审员。
IF 36.8 1区 医学 Q1 Medicine Pub Date : 2023-12-20 DOI: 10.1128/cmr.00138-23
Graeme Forrest
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引用次数: 0
The potential for development of clinically relevant microbial resistance to rifaximin-α: a narrative review. 利福昔明-α临床相关微生物耐药的发展潜力:叙述性回顾。
IF 36.8 1区 医学 Q1 Medicine Pub Date : 2023-12-20 Epub Date: 2023-11-16 DOI: 10.1128/cmr.00039-23
Herbert L DuPont

Rifaximin-α is a gut-targeted antibiotic indicated for numerous gastrointestinal and liver diseases. Its multifaceted mechanism of action goes beyond direct antimicrobial effects, including alterations in bacterial virulence, cytoprotective effects on host epithelial cells, improvement of impaired intestinal permeability, and reduction of proinflammatory cytokine expression via activation of the pregnane X receptor. Rifaximin-α is virtually non-absorbed, with low systemic drug levels contributing to its excellent safety profile. While there are high concentrations of drug in the colon, low water solubility leads to low colonic drug bioavailability, protecting the gut microbiome. Rifaximin-α appears to be more active in the bile-rich small bowel. Its important biologic effects are largely at sub-inhibitory concentration. Although in vitro testing of clinical isolates from rifaximin recipients has revealed rifaximin-resistant strains in some studies, the risk of emergent rifaximin-α resistance appears to be lower than for many other antibiotics. Rifaximin-α has been used for many years for traveler's diarrhea with no apparent increase in resistance levels in causative pathogens. Further, rifaximin-α retains its efficacy after long-term and recurrent usage in chronic gastrointestinal disorders. There are numerous reasons why the risk of microbial resistance to rifaximin-α may be lower than that for other agents, including low intestinal bioavailability in the aqueous colon, the mechanisms of action of rifaximin-α not requiring inhibitory concentrations of drug, and the low risk of cross transmission of rifaximin-α resistance between bacterial species. Reported emergence of vancomycin-resistant Enterococcus in liver-disease patients maintained on rifaximin needs to be actively studied. Further studies are required to assess the possible correlation between in vitro resistance and rifaximin-α efficacy.

利福昔明-α是一种肠道靶向抗生素,适用于多种胃肠道和肝脏疾病。其多方面的作用机制超越了直接的抗菌作用,包括改变细菌毒力,对宿主上皮细胞的细胞保护作用,改善受损的肠通透性,以及通过激活妊娠X受体减少促炎细胞因子的表达。利福昔明-α几乎不被吸收,具有较低的全身药物水平,有助于其良好的安全性。虽然在结肠中存在高浓度的药物,但低水溶性导致结肠药物生物利用度低,从而保护肠道微生物群。利福昔明-α似乎在富含胆汁的小肠中更活跃。其重要的生物效应主要是在亚抑制浓度。尽管对利福昔明接受者的临床分离株进行的体外测试在一些研究中发现了利福昔明耐药菌株,但出现利福昔明-α耐药的风险似乎低于许多其他抗生素。利福昔明-α多年来一直用于旅行者腹泻,在致病病原体的耐药水平没有明显增加。此外,利福昔明-α在长期和反复使用慢性胃肠道疾病后仍保持其疗效。微生物对利福昔明-α的耐药风险可能低于其他药物的耐药风险有很多原因,包括在水结肠中的肠道生物利用度低,利福昔明-α的作用机制不需要药物的抑制浓度,以及利福昔明-α耐药性在细菌物种之间交叉传播的风险低。据报道,在利福昔明维持治疗的肝病患者中出现万古霉素耐药肠球菌需要积极研究。需要进一步的研究来评估体外耐药性与利福昔明-α疗效之间可能的相关性。
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引用次数: 0
Virulence attributes of successful methicillin-resistant Staphylococcus aureus lineages. 成功耐甲氧西林金黄色葡萄球菌谱系的毒力特性。
IF 36.8 1区 医学 Q1 Medicine Pub Date : 2023-12-20 Epub Date: 2023-11-20 DOI: 10.1128/cmr.00148-22
Jhih-Hang Jiang, David R Cameron, Cara Nethercott, Marta Aires-de-Sousa, Anton Y Peleg

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of severe and often fatal infections. MRSA epidemics have occurred in waves, whereby a previously successful lineage has been replaced by a more fit and better adapted lineage. Selection pressures in both hospital and community settings are not uniform across the globe, which has resulted in geographically distinct epidemiology. This review focuses on the mechanisms that trigger the establishment and maintenance of current, dominant MRSA lineages across the globe. While the important role of antibiotic resistance will be mentioned throughout, factors which influence the capacity of S. aureus to colonize and cause disease within a host will be the primary focus of this review. We show that while MRSA possesses a diverse arsenal of toxins including alpha-toxin, the success of a lineage involves more than just producing toxins that damage the host. Success is often attributed to the acquisition or loss of genetic elements involved in colonization and niche adaptation such as the arginine catabolic mobile element, as well as the activity of regulatory systems, and shift metabolism accordingly (e.g., the accessory genome regulator, agr). Understanding exactly how specific MRSA clones cause prolonged epidemics may reveal targets for therapies, whereby both core (e.g., the alpha toxin) and acquired virulence factors (e.g., the Panton-Valentine leukocidin) may be nullified using anti-virulence strategies.

耐甲氧西林金黄色葡萄球菌(MRSA)是导致严重且经常致命感染的主要原因。耐甲氧西林金黄色葡萄球菌的流行是一波又一波地发生的,在这种情况下,以前成功的谱系被更适合和更好适应的谱系所取代。医院和社区环境中的选择压力在全球范围内并不统一,这导致了地理上不同的流行病学。这篇综述的重点是在全球范围内引发当前MRSA主流谱系的建立和维持的机制。虽然抗生素耐药性的重要作用将贯穿始终,但影响金黄色葡萄球菌在宿主内定植和致病能力的因素将是本综述的主要重点。我们表明,虽然MRSA拥有包括α毒素在内的多种毒素,但一个谱系的成功不仅仅涉及产生损害宿主的毒素。成功通常归因于与定植和生态位适应有关的遗传元件的获得或丢失,例如精氨酸分解代谢移动元件,以及调节系统的活性,并相应地转移代谢(例如,辅助基因组调节因子,agr)。准确了解特定的MRSA克隆如何引起长期流行可能会揭示治疗的靶点,因此核心(例如α毒素)和获得性毒力因子(例如潘通-瓦伦丁杀白细胞素)都可以通过抗毒策略无效。
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引用次数: 0
Invasive fusariosis. 侵袭性镰刀菌病。
IF 19 1区 医学 Q1 MICROBIOLOGY Pub Date : 2023-12-20 Epub Date: 2023-11-08 DOI: 10.1128/cmr.00159-22
Marcio Nucci, Elias Anaissie

Invasive fusariosis is a serious invasive fungal disease, affecting immunocompetent and, more frequently, immunocompromised patients. Localized disease is the typical clinical form in immunocompetent patients. Immunocompromised hosts at elevated risk of developing invasive fusariosis are patients with acute leukemia receiving chemotherapeutic regimens for remission induction, and those undergoing allogeneic hematopoietic cell transplant. In this setting, the infection is usually disseminated with positive blood cultures, multiple painful metastatic skin lesions, and lung involvement. Currently available antifungal agents have poor in vitro activity against Fusarium species, but a clear-cut correlation between in vitro activity and clinical effectiveness does not exist. The outcome of invasive fusariosis is largely dependent on the resolution of immunosuppression, especially neutrophil recovery in neutropenic patients.

SUMMARYInvasive镰刀菌病是一种严重的侵袭性真菌疾病,影响免疫功能低下的患者,更常见的是影响免疫功能受损的患者。局限性疾病是免疫功能低下患者的典型临床表现。发生侵袭性镰刀菌病风险较高的免疫受损宿主是接受化疗方案诱导病情缓解的急性白血病患者,以及接受异基因造血细胞移植的患者。在这种情况下,感染通常伴有阳性血液培养、多处疼痛的转移性皮肤病变和肺部受累。目前可用的抗真菌药物对镰刀菌属的体外活性较差,但体外活性和临床有效性之间并不存在明确的相关性。侵袭性镰刀菌病的结果在很大程度上取决于免疫抑制的解决,尤其是中性粒细胞减少患者的中性粒细胞恢复。
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引用次数: 0
Biofilm antimicrobial susceptibility testing: where are we and where could we be going? 生物膜抗菌药物敏感性测试:我们在哪里,我们可以去哪里?
IF 19 1区 医学 Q1 MICROBIOLOGY Pub Date : 2023-12-20 Epub Date: 2023-10-09 DOI: 10.1128/cmr.00024-23
Tom Coenye

Our knowledge about the fundamental aspects of biofilm biology, including the mechanisms behind the reduced antimicrobial susceptibility of biofilms, has increased drastically over the last decades. However, this knowledge has so far not been translated into major changes in clinical practice. While the biofilm concept is increasingly on the radar of clinical microbiologists, physicians, and healthcare professionals in general, the standardized tools to study biofilms in the clinical microbiology laboratory are still lacking; one area in which this is particularly obvious is that of antimicrobial susceptibility testing (AST). It is generally accepted that the biofilm lifestyle has a tremendous impact on antibiotic susceptibility, yet AST is typically still carried out with planktonic cells. On top of that, the microenvironment at the site of infection is an important driver for microbial physiology and hence susceptibility; but this is poorly reflected in current AST methods. The goal of this review is to provide an overview of the state of the art concerning biofilm AST and highlight the knowledge gaps in this area. Subsequently, potential ways to improve biofilm-based AST will be discussed. Finally, bottlenecks currently preventing the use of biofilm AST in clinical practice, as well as the steps needed to get past these bottlenecks, will be discussed.

摘要在过去的几十年里,我们对生物膜生物学的基本方面,包括生物膜抗菌敏感性降低背后的机制的了解急剧增加。然而,到目前为止,这些知识还没有转化为临床实践的重大变化。尽管生物膜的概念越来越受到临床微生物学家、医生和医疗保健专业人员的关注,但临床微生物学实验室中研究生物膜的标准化工具仍然缺乏;其中一个特别明显的领域是抗微生物药敏试验(AST)。人们普遍认为,生物膜的生活方式对抗生素的易感性有巨大影响,但AST通常仍在浮游细胞中进行。除此之外,感染部位的微环境是微生物生理学和易感性的重要驱动因素;但这在当前的AST方法中反映得很差。本综述的目的是概述生物膜AST的技术现状,并强调该领域的知识差距。随后,将讨论改进基于生物膜的AST的潜在方法。最后,将讨论目前阻碍生物膜AST在临床实践中使用的瓶颈,以及克服这些瓶颈所需的步骤。
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引用次数: 0
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