四环素类抗生素的复苏

摘要：四环素类抗生素是20世纪40年代发现的一类新型的抗生素。1948年第一个四环素类抗生素金霉素被应用于临床， 随着这类抗生素在临床和非临床上的大量使用，细菌耐药性不断增加、不可避免的不良反应以及其他新型抗生素的诞生，四环 素类抗生素的临床地位逐渐降低。20世纪70年代，第二代四环素类抗生素的米诺环素诞生了，因为其对耐药菌有效而在临床上 受到青睐。特别是在2005年，对多种耐药株具有较好活性的第三代四环素类抗生素替加环素被FDA批准上市，之后又经过了13 年，2018年FDA(Food and Drug Administration)同时批准了3种新型第三代四环素类抗生素上市，使得四环素类抗生素重新进入了 公众的视野。本文主要就第三代四环素类抗生素的抗微生物活性，化学结构特性、作用机制与抗耐药性，以及药物的临床研究 等方面进行综述。     

四环素衍生物合成的研究进展

四环素类抗生素的广泛应用导致其耐药菌大量产生,必须对其结构进行适当的修饰以改善性能。现综述四环素类抗生素的抗菌作用及耐药机制,并简要列举采用半合成,生物合成与全合成法进行结构修饰的研究进展。已报道的许多四环素衍生物在扩展抗菌谱、增强抗菌活性及克服耐药性方面都有所提高,而对四环素的结构简化,可保留其作为骨靶向药物载体或中枢神经保护性等非抗菌方面功能。     

四环素类抗生素实验室再度评价

四环素类抗生素是临床上常用抗生素之一。近年来,国内外临床反映其疗效较差,细菌对四环素的耐药现象严重。为了对四环素类抗生素的临床应用进行确切评价,我省于1983年在浙江省和杭州市一些医院的临床上分离到195株致病菌,进行了对四环素碱和盐酸盐、土霉素碱和盐酸盐、强力霉素和庆大霉素的药敏测定。结果表明195株致病菌中对四环素碱和盐酸盐及土霉素碱和盐酸盐的耐药率分别为85.13、82.57. 88.72、86.67(％),其中金黄色葡萄球菌的耐药率分别为75.64、69.23、83.33、80.77(％)。强力霉素的体外抗菌活性较高于四环素,并能抑制大部分金黄色葡萄球菌,其抑制率达86.67％,庆大霉素能抑制52％的细菌生长,并且也能抑制大部分金黄色葡萄球菌。 实验结果并根据四环素和土霉素的生物利用度,说明四环素和土霉素不宜作为常用抗菌药物,但可用于敏感菌感染引起的疾病。而强力霉素对尚可选用于葡萄球菌所致的一般感染。     

美满霉素的药理作用及临床应用

美满霉素(Minocyclin Hydrochloride,Mino)盐酸二甲胺四环素,是一种四环素的半合成衍生物。 药理作用及特点 抗菌谱和抗菌机理与四环素相同,抗菌作用显著强于四环素、土霉素、强力霉素,特别对耐药菌有效。包括对四环素类抗生素,青霉素类耐药的金葡菌、链球菌、大肠杆菌等。尤其沙眼依原体、尿素原生质、立克次体、螺旋体、厌氧菌对本品敏感。     

四环素类抗生素的实验室评价

四环素类抗生素是临床上常用抗生素之一,其口服制剂在国内应用极广。但近年来发现其疗效差,细菌对四环素族的耐药现象严重。为了对四环素族的临床应用进行确切评价,我室在1979～1981年间收集上海市区及郊县临床分离的革兰氏阳性菌、苹兰氏阴性菌和厌氧菌共605株,对它们进行了四环素和强力霉素的药敏测定。结果显示88％的菌株对四环素耐药,金葡菌的耐药率达82.2％,大肠杆菌、痢疾杆菌、产气杆菌、变形杆菌、肺炎杆菌等对四环素的耐药率均达70～90％以上。强力霉素的体外抗菌活性略高于四环素,大多数金葡菌对本品敏感,敏感率为81.2％,对四环素耐药者仍可对强力霉索敏感。测定四环素、土霉素和强力霉素各种口服制剂的生物利用度,发现四环素盐酸盐的生物利用度低,口服1g后血浓度低于对大多数常见致病菌的最低抑菌浓度(MIC),其他四环素和土霉素口服制剂的生物利用度更低于四环素盐酸盐,提示四环素口服制剂尤其是四环素碱已不宜作为临床上大多数常见致病菌感染的选用药物;其主要指征为某些病原如立克次体、衣原体、布氏杆菌等所致的各种感染,而强力霉素则尚可选用于葡萄球菌所致的一般感染。     

高效毛细管电泳分离四环素类抗生素及测定四环素中杂质

采用高效毛细管电泳法将四环素、４差向四环素、脱水四环素、脱水差向四环素、二甲胺四环素、去甲基金霉素及土霉素完全分离，并测定了四环素中杂质。结果表明，方法简便、高效、快速，所分析样品中，仅查有差向四环素，为四环素类抗生素中杂质的测定提供了一种新方法。     

四环素类药物对骨质疏松症的作用

四环素类抗生素 (tetracyclines)在本世纪 5 0年代开始用于临床 ,是个应用较早的广谱抗生素家族 ,包括四环素(tetracycline)、米诺环素 (minocycline)、强力霉素 (doxycy cline)、土霉素 (oxytetracycline)、金霉素 (chlortetracycline)、美他环素 (metacycline)、去甲金霉素 (demeclocycline)等品种。它们抗菌谱极广 ,除对革兰氏阳性菌和阴性菌有作用外 ,对立克次体、衣原体、支原体、螺旋体亦有抑制作用。但由于四环素类抗生素的大量使用 ,对四环素类耐药菌株日渐增多[1] ,有益于健康的菌丛 (healthyflora) ,如肠道菌丛等 ,大量减少或被消…     

喹诺酮类药物与其它抗菌药物体外抗枝原体活性研究

用微量稀释法比较了氧氟沙星、环丙沙星等喹诺酮化合物及大环内酯、四环素类抗生素体外抗枝原体活性，结果显示：对于解脲尿枝原体（Ｕｕ）、人型枝原体（Ｍｈ）、口腔枝原体（Ｍｏｒａ）和唾液枝原体（Ｍｓａｌ），喹诺酮类药物有中等抑制活性：氧氟沙星＞环丙沙星＞诺氟沙星＞萘啶酸；枝原体对大环内酯类抗生素高度敏感，其中交沙霉素活性最强，对Ｕｕ、Ｍｈ、Ｍｏｒａ、Ｍｓａｌ的ＭＩＣ分别为０．１２５、０．１２５、０．００７８和０．０１５６ｍｇ／Ｌ；四环素类抗生素中多西环素活性又大于四环素，对上述４种枝原体的ＭＩＣ分别是四环素的１／２～１／８倍。Ｕｕ、Ｍｈ对四环素和１４元大环内酯类抗生素红霉素易产生耐药性，对１６元大环内酯类抗生素交沙霉素、吉他霉素、泰洛星及喹诺酮类药物则相对不易产生耐药性。但对Ｍｈ，经喹诺酮类药物１０次诱导，ＭＩＣ增大８倍，呈现一定的耐药性。Ｕｕ、Ｍｈ的四环素或红霉素耐药株对红霉素或四环素有交叉耐药性，而对喹诺酮类药物、１６元大环内酯类抗生素则无交叉耐药性     

二甲胺四环素和强力霉素的临床应用

大多数细菌感染可用青霉素、头孢菌素和氨基糖苷类抗生素治疗,临床上已很少使用四环素。但在不少感染性疾病中四环素类药物仍有其独特的疗效。本文简要介绍半合成四环素类二甲胺四环素(MINO)和强力霉素(DOXY)的抗菌作用特点及其某些重要适应症。四环素可透过细胞膜作用于核糖体而阻碍蛋白的合成。细菌核糖体对药物的敏感性为动物细胞核糖体的100～1000倍,故在一定剂量下药物对细菌有选择作用。耐药机理是:耐药     

6-硫杂四环素的全合成

6-硫杂四环素(6-thiatetracycline),简称6-STC,抗菌谱范围比其它所有已知四环素类抗生素更广,居医学上重要的新四环素抗生素的首位。     

New developments in tetracycline antibiotics: glycylcyclines and tetracycline efflux pump inhibitors.

The tetracyclines, discovered in the 1940s, are a well-established class of antibiotics that still have a role in treating microbial infections in man. However, the widespread emergence of bacterial resistance due to efflux and ribosomal protection mechanisms has severely limited their effectiveness. A new generation of tetracyclines, the glycylcyclines, has been developed to overcome resistance to earlier tetracyclines. One of the new glycylcyclines, 9-t-butylglyclamido-minocycline (GAR-936, tigecycline) is currently undergoing clinical trials. This review considers the current status of glycylcyclines and the possibility that resistance to these agents might arise in the future. Other approaches are also being taken to address the emergence of resistance to tetracyclines. Recently, a number of tetracycline efflux pump inhibitors have been discovered that might be used in combination with earlier tetracyclines to restore their activity against resistant organisms. However, the development of tetracycline efflux pump inhibitors is complicated by the occurrence of several efflux pump sub-families and by the presence of both efflux and ribosomal protection mechanisms in the same organism, especially in naturally occurring, Gram-positive clinical isolates.     

Tetracyclines-extending the atypical spectrum

The main features and the present position of tetracyclines are reviewed. The mechanism of their action, bacterial resistance and the most recent findings are reported. Their decreased use is due to the availability of new, active, better-tolerated antibiotics. However, tetracyclines still have a place in the treatment of chlamydial and rickettsial infections, brucellosis and Lyme disease. In respiratory infections, they can be employed when necessary in infections caused by Chlamydia psittaci, C. pneumoniae, Mycoplasma pneumoniae, and also by Streptococcus pneumoniae and Haemophilus influenzae, whose rates of resistance now seem lower than in the past when tetracyclines were more largely prescribed.     

Antimicrobial spectrum, pharmacology and therapeutic use of antibiotics. Part 1: tetracyclines.

The mode of action, bacterial resistance, in vitro activity, pharmacology, dosage, adverse reactions, interactions and indications for tetracyclines are reviewed. Suggestions for the selection of a particular tetracycline are provided. It is concluded that there is only one pertinent difference among the tetracyclines, namely, that doxycycline, and probably minocycline, can be given in full dosage and with minimal risk to patients with renal impairment.     

An update on tetracyclines

The tetracyclines are a family of related natural products that were originally discovered by virtue of their antibacterial activities. As one of the earliest antibiotics to be marketed after penicillin and streptomycin, and because of their convenient oral dosing, tetracyclines have achieved wide clinical usage. However, this widespread clinical use, in addition to their use in animal feed, and even as an antibiotic spray for fruit and other crops, has produced widespread resistance that ultimately has limited the clinical utility of the entire family of tetracycline antibiotics. More recently, however, there has been renewed interest in this antibiotic class, with attempts being made to identify compounds capable of evading common bacterial resistance mechanisms and to search for potential uses beyond antibacterial therapy. This review will discuss the identification of 9-glycylamido-tetracyclines (glycylcyclines) and related compounds that have successfully evaded most bacterial resistance mechanisms, resulting in the approval of the first glycylcycline, tigecycline, for clinical use.     

Recent developments in tetracycline antibiotics

The rapid emergence of pathogenic bacteria resistant to tetracyclines and other currently available antibiotics has caused serious concern among medical professionals. It has heightened resurgent interest in studying the mechanisms of resistance and in developing new antibiotics. A comprehensive review has outlined the developments of tetracyclines prior to 1980 [47]. This review will highlight the pertinent advances in the tetracycline field during the last two decades, including recent progress on elucidating the mechanisms of resistance, and the development of novel tetracyclines to combat bacterial resistance. Most of the new tetracycline derivatives described in this review have been either prepared semisynthetically or isolated from fermentation. In the semisynthetic area, efflux inhibitors that are effective in an in vitro model have been identified. A new class of tetracyclines, named glycylcyclines has been the subject of numerous reports, and will be the major focus of this review. The glycylcyclines are currently the only derivatives that exhibit antibacterial activity comparable to that of the early tetracyclines when they were first introduced. These compounds show potent activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including strains that carry the two major tetracycline-resistance determinants, efflux and ribosomal protection. Two of the glycylcycline derivatives. DMG-MINO and DMG-DMDOT, have been studied by several groups of investigators against a large number of clinical pathogens isolated from various sources. The spectrum of activity of these compounds includes organisms with resistance to antibiotics other than tetracyclines, e.g., methicillin-resistant staphylococci, penicillin-resistant streptococcus pneumoniae, and vancomycin-resistant enterococci. Their in vitro, as well as in vivo activity against bacteria with characterized tetracycline- or minocycline-resistant elements will be summarized. The structure-activity relationships of glycylcyclines and their mode of action will also be discussed.     

The glycylcyclines: a comparative review with the tetracyclines

The tetracycline class of antimicrobials exhibit a broad-spectrum of activity against numerous pathogens, including Gram-positive and Gram-negative bacteria, as well as atypical organisms. These compounds are bacteriostatic, and act by binding to the bacterial 30S ribosomal subunit and inhibiting protein synthesis. The tetracyclines have been used successfully for the treatment of a variety of infectious diseases including community-acquired respiratory tract infections and sexually transmitted diseases, as well in the management of acne. The use of tetracyclines for treating bacterial infections has been limited in recent years because of the emergence of resistant organisms with efflux and ribosomal protection mechanisms of resistance. Research to find tetracycline analogues that circumvented these resistance mechanisms has lead to the development of the glycylcyclines. The most developed glycylcycline is the 9-tert-butyl-glycylamido derivative of minocycline, otherwise known as tigecycline (GAR-936). The glycylcyclines exhibit antibacterial activities typical of earlier tetracyclines, but with more potent activity against tetracycline-resistant organisms with efflux and ribosomal protection mechanisms of resistance. The glycylcyclines are active against other resistant pathogens including methicillin-resistant staphylococci, penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci. Tigecycline is only available in an injectable formulation for clinical use unlike currently marketed tetracyclines that are available in oral dosage forms. Tigecycline has a significantly larger volume of distribution (> 10 L/kg) than the other tetracyclines (range of 0.14 to 1.6 L/kg). Protein binding is approximately 68%. Presently no human data are available describing the tissue penetration of tigecycline, although studies in rats using radiolabelled tigecycline demonstrated good penetration into tissues. Tigecycline has a half-life of 36 hours in humans, less than 15% of tigecycline is excreted unchanged in the urine. On the basis of available data, it does not appear that the pharmacokinetics of tigecycline are markedly influenced by patient gender or age. The pharmacodynamic parameter that best correlates with bacteriological eradication is time above minimum inhibitory concentration. Several animal studies have been published describing the efficacy of tigecycline. Human phase 1 and 2 clinical trials have been completed for tigecycline. Phase 2 studies have been conducted in patients with complicated skin and skin structure infections, and in patients with complicated intra-abdominal infections have been published as abstracts. Both studies concluded that tigecycline was efficacious and well tolerated. Few human data are available regarding the adverse effects or drug interactions resulting from tigecycline therapy; however, preliminary data report that tigecycline can be safely used, is well tolerated and that the adverse effects experienced were typical of the tetracyclines (i.e. nausea, vomiting and headache). Tigecycline appears to be a promising new antibacterial based on in vitro and pharmacokinetic/pharmacodynamic activity; however more clinical data are needed to fully evaluate its potential.     

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.     

我院胸外科2003年与2005年细菌药敏对比分析

目的:通过对比我院胸外科在《抗菌药物临床应用指导原则》出台前后两年,即2003年与2005年的细菌药敏数据,分析临床控制使用抗菌药物的效果。方法:采用回顾性分析方法采集2003年和2005年病原菌分布情况和药敏数据,将两年数据进行对比分析。结果:革兰阴性菌菌株数2005年较2003年有明显的下降,各细菌耐药率也有不同程度的下降,特别是大肠埃希菌、阴沟杆菌耐药率下降明显,但铜绿色假单胞菌对三代和四代头孢菌素耐药率有一定的上升;革兰阳性菌中金黄色葡萄球菌菌株数明显下降,溶血葡萄球菌菌株数有一定下降,但表皮葡萄球菌有明显上升;表皮葡萄球菌、金黄色葡萄球菌耐药率2005年较2003年有较明显下降,特别是对克林霉素、四环素、磺胺类药物耐药率有明显下降。结论:以《抗菌药物临床应用指导原则》出台为契机,加强临床抗菌药物管理有益于降低临床感染发生率和细菌耐药性。