大环内酯类抗生素的作用机制、耐药机制与控制措施

作为抗生素家族的重要成员之一,大环内酯类抗生素因其抗菌活性强、抗菌谱广、疗效显著和不易产生耐药性等优点而被广泛应用到临床.随着大环内酯类抗生素临床应用的增多,细菌对其耐药性也逐渐上升,因此对大环内酯类抗生素的作用机制、耐药机制及控制措施的研究已成为热点.     

大环类酯类抗菌药物的分类及研究进展

大环内酯类抗生素是一类具有大环内酯这一基本化学结构和相似抗菌谱的抗菌药物。大环内酯类抗生素主要作用于革兰阳性菌和阴性球菌、厌氧菌、军团菌、衣原体和支原体细菌等,在临床治疗中发挥了重要作用。本文就大环内酯类药物的发展历史和分类进行了综述,并对临床上常用的几种动物专用大环内酯类抗生素进行简单介绍。     

大环内酯类抗生素对细菌生物被膜作用的研究进展

细菌生物被膜(BBF)是一类由生物大分子包裹细菌而形成的具有特殊复杂结构的微克隆多细胞群体,由其感染所引起的疾病具有迁延不愈、反复发作等特点,在临床上有较大危害性。当前临床上用于治疗细菌生物被膜疾病的药物主要集中于大环内酯类抗生素,文章综述了细菌生物被膜结构特点和大环内酯类抗生素的药效动力学,并将大环内酯类抗生素清除、抑制细菌生物被膜的主要机理归纳为阻碍细菌黏附过程、破坏细菌生物被膜基础结构和干扰细菌的群体感应系统。     

兽用头孢菌素类抗生素研究进展

头孢菌素类抗生素具有抗菌谱广、抗菌活性强等特点,在人类医学领域应用十分广泛。在兽医临床中,由于药物种类较少及不规范使用而易使细菌产生交叉耐药性,头孢菌素的应用受到一定程度的限制。文章围绕兽用头孢菌素的发展历程、作用机制、药物代谢动力学与安全性等方面,总结了畜禽专用头孢菌素主要种类、抗菌活性及其在动物体内的药动学参数,比较了兽用头孢菌素的抗菌活性,以及其对敏感菌感染疾病的治疗效果。同时概述了头孢菌素类抗生素耐药性产生机制与耐药现状,并分析比较了各国在此类药物耐药性控制中采取的举措。通过对兽用头孢菌素类抗生素的发展及临床应用进行综述,有利于促进头孢菌素在兽医临床中的科学规范使用。     

兽用头孢菌素类抗生素研究进展

头孢菌素类抗生素具有抗菌谱广、抗菌活性强等特点,在人类医学领域应用十分广泛。在兽医临床中,由于药物种类较少及不规范使用而易使细菌产生交叉耐药性,头孢菌素的应用受到一定程度的限制。文章围绕兽用头孢菌素的发展历程、作用机制、药物代谢动力学与安全性等方面,总结了畜禽专用头孢菌素主要种类、抗菌活性及其在动物体内的药动学参数,比较了兽用头孢菌素的抗菌活性,以及其对敏感菌感染疾病的治疗效果。同时概述了头孢菌素类抗生素耐药性产生机制与耐药现状,并分析比较了各国在此类药物耐药性控制中采取的举措。通过对兽用头孢菌素类抗生素的发展及临床应用进行综述,有利于促进头孢菌素在兽医临床中的科学规范使用。     

细菌耐药性产生对毒力影响的研究进展

抗菌药物如氟喹诺酮类、四环素类、大环内酯类、杆菌肽类和氨基糖苷类等广泛用于细菌所致疾病的治疗,然而抗菌药物的广泛应用导致药物对细菌选择性压力不断增加,细菌耐药性也日益严重。尽管细菌耐药性和毒力基因发挥的作用不同,但是细菌对抗菌药物产生耐药性会对细菌的毒力具有一定的影响。本文将对细菌对氟喹诺酮类、四环素类、大环内酯类、杆菌肽类和氨基糖苷类药物耐药后对毒力的影响进行综述。     

兽用β-内酰胺类抗生素耐药性分析

β-内酰胺类抗生素（β-lactams）是指化学结构中具有β-内酰胺环的一大类抗生素,具有共同的抗菌作用机制,即抑制细菌细胞壁的合成,属于繁殖期杀菌药,主要包括青霉素类和头孢菌素类。此类抗生素具有杀菌活性强、毒性低、适应症广及临床疗效好等优点,一直以来在临床上视为抗感染的首选抗菌药物。     

间充质干细胞发挥抗菌作用的机制研究进展

对抗菌药物具有强耐药性的“超级细菌”对人和家畜健康造成巨大威胁。广泛、高频使用种类有限的抗菌药物治疗人、家畜以及宠物细菌感染性疾病是产生“超级细菌”的根源。寻找现有常规抗菌药物的替代品或增强剂是当前热点研究方向之一。研究表明,间充质干细胞（mesenchymal stem cells,MSCs）具有抗菌特性。理论上,MSCs有可能成为治疗细菌感染性疾病的有效手段。对MSCs影响细菌存活的作用机制以及抗菌药物可能对MSCs功能产生的影响等方面的研究进展进行综述,以期为进一步阐明MSCs抗菌作用机制、挖掘MSCs作为治疗细菌感染性疾病新方法的潜力提供参考。     

β-内酰胺酶抑制剂与β-内酰胺类抗生素联用在兽医学上的应用

20世纪40年代,第一个β-内酰胺类抗生素青霉素的研制和应用,开创了抗生素治疗细菌性疾病的光辉时代。但细菌的耐药性也因抗生素的广泛应用而变得日益普遍,细菌对β-内酰胺类抗生素最主要的耐药机制是产生β-内酰胺酶,破坏β-内酰胺环使抗生素失活。β-内酰胺酶抑制剂的研制应用,恢复了β-内酰胺类抗生素的有效性,使β-内酰胺类抗生素得以继续发挥其在临床上强大的治疗作用。本文主要综述了β-内酰抑制剂的作用机制及其与β-内酰胺类抗生素联用的抗菌活性,以及在兽医临床上的应用概况。为有效地应用β-内酰胺类抗生素控制耐药菌感染提供参考。     

替米考星的研究新进展及其应用

替米考星是一种动物专用的新型大环内酯类抗生素,临床主要应用于牛、猪、鸡、绵羊、山羊、兔等动物感染性疾病,特别是用于畜禽呼吸道疾病并取得显著疗效.该药具有抗菌活性强、药代动力学特征优良、用量少、毒性小等特点.临床应用表明:替米考星是一种安全有效的新型兽药,具有广阔的应用前景.     

Immuno-modulation and anti-inflammatory benefits of antibiotics: The example of tilmicosin

Exagerated immune responses, such as those implicated in severe inflammatory reactions, are costly to the metabolism. Inflammation and pro-inflammatory mediators negatively affect production in the food animal industry by reducing growth, feed intake, reproduction, milk production, and metabolic health. An ever-increasing number of findings have established that antibiotics, macrolides in particular, may generate anti-inflammatory effects, including the modulation of pro-inflammatory cytokines and the alteration of neutrophil function. The effects are time- and dose-dependent, and the mechanisms responsible for these phenomena remain incompletely understood. Recent studies, mostly using the veterinary macrolide tilmicosin, may have shed new light on the mode of action of some macrolides and their anti-inflammatory properties. Indeed, research findings demonstrate that this compound, amongst others, induces neutrophil apoptosis, which in turn provides anti-inflammatory benefits. Studies using tilmicosin model systems in vitro and in vivo demonstrate that this antibiotic has potent immunomodulatory effects that may explain why at least parts of its clinical benefits are independent of anti-microbial effects. More research is needed, using this antibiotic and others that may have similar properties, to clarify the biological mechanisms responsible for antibiotic-induced neutrophil apoptosis, and how this, in turn, may provide enhanced clinical benefits. Such studies may help establish a rational basis for the development of novel, efficacious, anti-microbial compounds that generate anti-inflammatory properties in addition to their antibacterial effects.     

Characterization of in vivo-acquired resistance to macrolides of Mycoplasma gallisepticum strains isolated from poultry

ABSTRACT: The macrolide class of antibiotics, including tylosin and tilmicosin, is widely used in the veterinary field for prophylaxis and treatment of mycoplasmosis. In vitro susceptibility testing of 50 strains of M. gallisepticum isolated in Israel during the period 1997-2010 revealed that acquired resistance to tylosin as well as to tilmicosin was present in 50% of them. Moreover, 72% (13/18) of the strains isolated from clinical samples since 2006 showed acquired resistance to enrofloxacin, tylosin and tilmicosin. Molecular typing of the field isolates, performed by gene-target sequencing (GTS), detected 13 molecular types (I-XIII). Type II was the predominant type prior to 2006 whereas type X, first detected in 2008, is currently prevalent. All ten type X strains were resistant to both fluoroquinolones and macrolides, suggesting selective pressure leading to clonal dissemination of resistance. However, this was not a unique event since resistant strains with other GTS molecular types were also found. Concurrently, the molecular basis for macrolide resistance in M. gallisepticum was identified. Our results revealed a clear-cut correlation between single point mutations A2058G or A2059G in domain V of the gene encoding 23S rRNA (rrnA, MGA_01) and acquired macrolide resistance in M. gallisepticum. Indeed, all isolates with MIC ≥ 0.63 μg/mL to tylosin and with MIC ≥ 1.25 μg/mL to tilmicosin possess one of these mutations, suggesting an essential role in decreased susceptibility of M. gallisepticum to 16-membered macrolides.     

红霉素与四环素耐药基因在猪链球菌临床分离株中的检测

为了解临床分离的48株猪链球菌对大环内酯类药物及四环素耐药基因的分布,用微量稀释法测定48株临床分离的猪链球菌对大环内酯类、四环素、β-内酰胺类及头孢类9种抗生素的药物敏感性,建立PCR方法对耐药菌株大环内酯类耐药基因ermA/B/C、mefA/E、msrD、mphB、23S rRNA,L4,L22和四环素耐药基因tetM、tetO、tetL、tetK及与Tn916转座子相关的int和xis基因进行检测。结果表明,31株2型猪链球菌中大环内酯类药物耐药率为3.23%,17株9型猪链球菌红霉素耐药率为88.24%,泰乐菌素、磷酸替米考星、阿奇霉素的耐药率均为70.59%。48株猪链球菌对四环素均耐药,但对青霉素、阿莫西林、头孢曲松钠、氨苄西林均敏感。大环内酯类耐药基因主要以ermB为主,占75%(12/16),mefA/E、msrD占25%(4/16),16株红霉素耐药菌株中,tetM、tetO、int、xis的检出率分别为25%(4/16)、62.5%(10/16)、31.25%(5/16)和31.25%(5/16),没有检测到ermA、ermC、mphB、tetL、tetK。所有红霉素耐药菌株均未检测到23S rRNA、L4和L22突变。     

利血平对化脓隐秘杆菌大环内酯类外排基因mefA表达的影响

化脓隐秘杆菌(Trueperella pyogenes,T.pyogenes)是一种能够引起动物和人化脓性感染的重要病原菌。随着抗生素的广泛使用,该菌已对临床常用的大环内酯类、四环素类等药物产生不同程度的耐药性。本试验拟探讨外排泵抑制剂利血平对T.pyogenes大环内酯类外排基因mefA mRNA及蛋白表达的影响,将为细菌外排泵抑制剂的研究奠定理论基础。以携带mefA基因的T.pyogenes分离株(17,20号)为试验菌株,采用荧光定量PCR及Western blot技术,检测利血平作用前后各菌株mefA基因mRNA及蛋白表达量。结果表明,1/2 MIC利血平作用2株耐药菌株36 h后,大环内酯类抗生素红霉素、罗红霉素、泰乐菌素、阿奇霉素和替米考星对携带mefA基因的T.pyogenes的MIC值均有不同程度的降低。17和20号分离株外排基因mefA mRNA表达水平较药物作用前均极显著降低(利血平作用前是作用后的5.18,17.54倍),外排蛋白MefA表达量较药物作用前也显著降低(利血平作用前是作用后的1.08,1.70倍),且基因水平和蛋白水平的变化与其耐药表型的变化趋势一致;提示利血平可能是通过抑制外排基因mefA的转录和翻译而消减T.pyogenes对大环内酯类抗生素的耐药性。     

Macrolide antibiotics, drug interactions and microsomal enzymes: implications for veterinary medicine

The macrolide group of antibiotics includes natural members, pro-drugs and semi-synthetic derivatives, thus named because they are composed of a large aglycone ring (from 14 to 16 carbon atoms), to which are attached several sugars. Some of them are amino-sugars, containing a diethylamino, tertiary amine function. A number of antibiotics, including erythromycin, oleandomycin, triacetyl-oleandomycin (troleandomycin), carbomycin, spiramycin, tylosin, rosamicin, azithromycin, clarithromycin, dirithromycin and others, are members of this group. On a comparative basis, erythromycin and oleandomycin are similar, with the same basic 14-carbon lactone ring and side chain sugars. The remaining compounds contain a basic 15- or 16-carbon lactone ring and one or two side-chain sugars. Most of the macrolides are produced by Streptomyces spp bacteria. An exception is rosamicin, which is produced by Micromonospora. Clarithromycin and azithromycin are new semi-synthetic derivatives of erythromycin.     

靶向抗菌肽的设计策略与应用

抗生素问世以来挽救了无数生命，然而近年来抗生素的滥用越来越严重，从而导致多重耐药菌的出现以及机体正常微生物群落的生态失衡等问题，迫使人们开始寻找有效的抗生素替代物。抗菌肽广泛存在于动植物体中，具有抗菌、抗肿瘤、抗病毒及免疫调节等生物学活性，且不易诱发细菌耐药性，在临床和畜牧生产中表现出极好的应用前景。为避免细菌耐药性和微生态紊乱等问题的产生，具有靶向功能的抗菌肽受到科研工作者的青睐，逐渐成为研究的热点，并有望成为抗生素替代物之一。本文对近年来靶向抗菌肽的设计思路及其在临床和畜牧生产中的应用前景进行概述，以期为将来靶向抗菌肽的开发提供新的思路。     

In vitro development of resistance to enrofloxacin,erythromycin, tylosin,tiamulin and oxytetracycline in Mycoplasma gallisepticum,Mycoplasma iowae and Mycoplasma synoviae

The in vitro emergence of resistance to enrofloxacin, erythromycin, tylosin, tiamulin, and oxytetracycline in three avian Mycoplasma species, Mycoplasma gallisepticum, Mycoplasma synoviae and Mycoplasma iowae was studied. Mutants were selected stepwise and their MICs were determined after 10 passages in subinhibitory concentrations of antibiotic. High-level resistance to erythromycin and tylosin developed within 2-6 passages in the three Mycoplasma species. Resistance to enrofloxacin developed more gradually. No resistance to tiamulin or oxytetracycline could be evidenced in M. gallisepticum or M. synoviae after 10 passages whereas, resistant mutants were obtained with M. iowae. Cross-sensitivity tests performed on mutants demonstrated that mycoplasmas made resistant to tylosin were also resistant to erythromycin, whereas mutants made resistant to erythromycin were not always resistant to tylosin. Some M. iowae tiamulin-resistant mutants were also resistant to both macrolide antibiotics. Enrofloxacin and oxytetracycline did not induce any cross-resistance to the other antibiotics tested. These results show that Mycoplasma resistance to macrolides can be quickly selected in vitro, and thus, providing that similar results could be obtained under field conditions, that development of resistance to these antibiotics in vivo might also be a relatively frequent event.     

动物性食品中头孢噻呋残留检测研究

头孢噻呋是一种作用强、抗菌谱广的抗生素熏近年来,在兽医临床治疗上的应用日趋广泛熏其在动物组织或其产品中的残留也引起了人们的关注。笔者就动物性食品中头孢噻呋残留检测的方法和概况作一综述。     

The use of macrolides, lincomycin and tiamulin as animal feed drugs for pigs in Schleswig-Holstein

An evaluation of production orders for medicated feedingstuffs for pigs given in 1998 in Schleswig-Holstein showed macrolides, lincomycin and tiamulin as frequently used antibiotical ingredients. The presented study analyses the production orders which include macrolides, lincomycin or tiamulin in more detail. There were large deviations to the rules of good clinical practise for the use of antibiotics (2000). The applied dosage was often lower than suggested in the literature.     

卵黄抗体及其在疾病防制与饲料中的应用研究进展

卵黄抗体（immunoglobulin of yolk,IgY）具有性质稳定、制备简单、产量高、成本低等优点,已广泛用于动物的疾病防制,随着抗生素的禁用,卵黄抗体逐渐成为一种新型饲料添加剂在饲料中添加应用。作者就卵黄抗体的特征及其在动物疾病防制与饲料中的应用进行了简要概述。