喹诺酮类药物的作用机制耐药机制及研究进展

喹诺酮类药物主要作用于DNA拓扑异构酶,阻碍DNA复制,发挥广谱抗菌作用。但该类药物的耐药问题日益严重,耐药菌株频现。本文综述喹诺酮类药物的耐药机制及其研究进展。     

喹诺酮类药物的抗菌和细菌耐药机制

喹诺酮类药物是一类以1,4-二氢-4-氧-3-喹啉羧酸为基本结构的全合成抗菌药物。自其第一个产品萘啶酸发现以来,经约30年发展,一系列化合物相继问世,并在临床中得以广泛应用。随着这类药物不断涌现,其抗菌及细菌耐药机制研究也不断深入。本文就喹诺酮类药物的抗菌作用机制以及细菌对其耐药机制作一综述。     

氟喹诺酮类药物的研究进展

目的综述氟喹诺酮类药物的最新研究进展。方法对氟喹诺酮类药物抗菌作用及机制、耐药机制、不良反应、配伍禁忌等研究进展进行分类、归纳与总结。结果氟喹诺酮类药物具有不错的市场应用前景,但需注意可能的不良反应及耐药性的发生。结论氟喹诺酮类药物具有开发的可行性。     

氟喹诺酮类药物耐药性分析及合理应用

综述并分析氟喹诺酮类药物的耐药机制及应用现状等。氟喹诺酮类药物的耐药机制是多样的,耐药现象严重。临床在设计氟喹诺酮类药物给药方案时,除应重视抗菌谱、感染源等多种因素外,还应综合考虑药物的有关参数,做到控制感染的同时,避免耐药菌株的出现。     

喹诺酮类药物的临床应用

喹诺酮类抗菌药物是一类全合成的抗菌药物,具有抗菌谱广、抗菌力强、作用机制独特、高效、低毒等特点.新型的喹诺酮类药物更是具有生物利用度高、半衰期长、血药浓度高、组织分布广等优点,广泛用于呼吸系统、消化系统感染性疾病的治疗.但是抗菌药物的临床应用增多,其耐药问题也日益突出.如何合理使用喹诺酮类药物是临床面临的重要问题.     

新喹诺酮类药物对革兰阳性菌的作用

喹诺酮类药物已迅速发展成为治疗感染性疾病最为有效的药物之一。尽管在20世纪80年代开发的环丙沙星等氟喹诺酮类药物对绝大多数革兰阴性菌具较强的抗菌作用,但对革兰阳性菌的活性仍有限。直至90年代才合成开发了几种对革兰阳性菌具良好抗菌活性的氟喹诺酮类抗菌药如司帕沙星、clinafloxacin(PD127391,CI960和AM-1091)和Bay y3118。本文对喹诺酮类药物抗革兰阳性菌的作用机制和细菌对其耐药机制作一综     

氟喹诺酮类药物的临床不良反应

喹诺酮类药物抑制细菌DNA旋转酶，使其不能降解螺旋而达到阻碍细菌DNA合成的目的，从而发挥其临床作用。因其作用机制独特，与其它抗生素无交叉耐药而受到欢迎，临床应用十分广泛。第三代喹诺酮类药物即氟喹诺酮类药物半衰期长，分布广，抗菌谱宽，抗菌活性强而成为临床上重要的一类抗感染药物。收集我院近年来临床应用氟喹诺酮类药物治疗细菌性感染的资料并对其不良反应进行分析总结。     

金属离子对喹诺酮活性影响的研究进展

喹诺酮类药物以抗菌活性强、抗菌谱广、疗效确切等优点被广泛应用于临床,一些研究结果表明金属离子对喹诺酮类药物的活性有一定的影响。本文概述了喹诺酮类药物的发展及作用机制,总结了金属离子对喹诺酮类的作用及喹诺酮类药物金属配合物的活性,最后展望了喹诺酮类药物今后的发展。     

喹诺酮类药物的合理使用

喹诺酮类药物以其抗菌谱广．抗菌作用强，剂型多样，使用方便，与其他抗菌药物之间交叉耐药现象较少等优势已被广泛用于治疗各种感染性疾病。然而，随着新的喹诺酮类抗菌药的不断问世，其耐药性与不良反应的报道日渐增多，如何合理地使用这类药物应引起重视。现就喹诺酮类药物的合理使用简述如下。     

哇诺酮类抗菌药的作用机制及细菌耐药性的研究进展

喹诺酮类抗菌药具有抗菌谱广,作用机制独特,药物动力学性能好以及口服和非肠道给药均有效等特点,在临床上广泛应用于各种感染的治疗.但是随着此类药物的使用,其耐药性亦不断增长,并已迅速发展至十分严重的程度.耐药性的大量出现与广泛传播会给人们的健康造成很大的危害,给临床治疗带来很大困难,甚至造成治疗失败,目前已引起了普遍重视.因此,深入研究喹诺酮类药物的作用机制,耐药机制,进而探索解决其耐药性的方法,开发新型喹诺酮类药物和具有抑制喹诺酮细菌耐药性的新药,以遏制或减缓此类药物细菌耐药性的发展已迫在眉睫.本文对近年来关于喹诺酮类抗菌药物的作用机制、耐药机制以及克服耐药性的对策等项的研究作一综述.     

喹诺酮类抗菌药的耐药性机制及研究进展

植物中的活性成分是植物药发挥疗效的物质基础,植物活性成分研究是阐释植物药的生物活性、临床疗效和毒性的必要手段,也是新药发现和创制的可行途径,更是中药药效物质基础研究、     

Fluorinated quinolones

Quinolones, chemically related to nalidixic acid, have a strong and rapid bactericidal action against Gram-negative bacteria, includingPs. aeruginosa, someMycobacteria, Legionella andStaphylococci. Streptococci and anaerobic bacteria are usually less sensitive. The quinolones exert their bactericidal action through inhibition of the enzyme DNA gyrase. Quinolones are absorbed for 50–100% from the gastro-intestinal tract, their volume of distribution is generally high (2 l/kg) and high concentrations are reached in almost all organs. The elimination half-lives range from 4 to 14 h. The efficacy of quinolones in urinary tract infections has been shown in many studies. They also seem to be effective in many serious infections. In animal studies their efficacy was generally equal or superior to aminoglycosides. Until now only mild and infrequent side effects have been reported.     

Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde

Quinolones are a very important family of antibacterial agents that are widely prescribed for the treatment of infections in humans. Although the founding members of this drug class had little clinical impact, successive generations include the most active and broad spectrum oral antibacterials currently in use. In contrast to most other anti-infective drugs, quinolones do not kill bacteria by inhibiting a critical cellular process. Rather, they corrupt the activities of two essential enzymes, DNA gyrase and topoisomerase IV, and induce them to kill cells by generating high levels of double-stranded DNA breaks. A second unique aspect of quinolones is their differential ability to target these two enzymes in different bacteria. Depending upon the bacterial species and quinolone employed, either DNA gyrase or topoisomerase IV serves as the primary cytotoxic target of drug action. While this unusual feature initially stymied development of quinolones with high activity against Gram-positive bacteria, it ultimately opened new vistas for the clinical use of this drug class. In addition to the antibacterial quinolones, specific members of this drug family display high activity against eukaryotic type II topoisomerases, as well as cultured mammalian cells and in vivo tumor models. These antineoplastic quinolones represent a potentially important source of new anticancer agents and provide an opportunity to examine drug mechanism across divergent species. Because of the clinical importance of quinolones, this review will discuss the mechanistic basis for drug efficacy and interactions between these compounds and their topoisomerase targets.     

武汉地区7家医院连续5年喹诺酮类药用药频度与细菌耐药性分析

目的：研究喹诺酮类抗菌药的用量与细菌耐药率之间的关系,促进临床合理用药。方法：回顾性调查武汉地区7家医院2005～2009年喹诺酮类抗菌药的用量,并与监测菌的耐药率做相关分析。结果：大多数监测菌种对喹诺酮类药的耐药率均超过30%;鲍曼不动杆菌对喹诺酮类药的耐药率随喹诺酮类药用量的变化而变化,与喹诺酮类药总用药频度高度相关。结论：喹诺酮类药对多数常见菌种的耐药率较高,其用药频度对细菌耐药性变异也有一定影响。应严格把握喹诺酮类药的临床适应证,加强对喹诺酮类药的管理,以减少或延缓细菌耐药性的发生。     

Section Review Anti-infectives: The future role of quinolones

Quinolones, such as ciprofloxacin and ofloxacin, have gained wide acceptance for the treatment of bacterial infections of the respiratory tract, urinary tract, skin and soft tissues, as well as sexually transmitted diseases. Good pharmacokinetic profiles and potent activities against a wide range of Gram-negative and Gram-positive pathogens result in the use of these antibacterials in both hospital and community settings. Although recently developed clinical quinolones dominate in the chemotherapy of various bacterial infections, their use is restricted by limited activities against a number of clinically-important Gram-positive bacteria such as Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and enterococci. Ciprofloxacin, the market leader, also has low potency against anaerobes. Bacterial resistance (such as in Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus) to ciprofloxacin is increasing rapidly. Many quinolone compounds are being synthesised to address these drawbacks. The new quinolones currently under development are characterised by enhanced activities against streptococci, staphylococci, enterococci and anaerobes. Although the treatment of traditional bacterial infections is at present the focus of quinolone research, the future role of quinolones will extend current applications to include new indications of bacterial infections and other non-bacterial diseases. This review will concentrate on the more recently developed quinolones which possess significantly more therapeutic value than existing quinolones, and will provide information on those compounds under commercial development with major therapeutic potential. Recent developments in research into the identification of quinolones for the treatment of tuberculous, cancer, viral, fungal infections and parasitic diseases will also be discussed.     

The history of the development and changes of quinolone antibacterial agents

The quinolones, especially the new quinolones (the 6-fluoroquinolones), are the synthetic antibacterial agents to rival the Beta-lactam and the macrolide antibacterials for impact in clinical usage in the antibacterial therapeutic field. They have a broad antibacterial spectrum of activity against Gram-positive, Gram-negative and mycobacterial pathogens as well as anaerobes. Further, they show good-to-moderate oral absorption and tissue penetration with favorable pharmacokinetics in humans resulting in high clinical efficacy in the treatment of many kinds of infections. They also exhibit excellent safety profiles as well as those of oral Beta-lactam antibiotics. The bacterial effects of quinolones inhibit the function of bacterial DNA gyrase and topoisomerase IV. The history of the development of the quinolones originated from nalidixic acid (NA), developed in 1962. In addition, the breakthrough in the drug design for the scaffold and the basic side chains have allowed improvements to be made to the first new quinolone, norfloxacin (NFLX), patented in 1978. Although currently more than 10,000 compounds have been already synthesized in the world, only two percent of them were developed and tested in clinical studies. Furthermore, out of all these compounds, only twenty have been successfully launched into the market. In this paper, the history of the development and changes of the quinolones are described from the first quinolone, NA, via, the first new quinolone (6-fluorinated quinolone) NFLX, to the latest extended-spectrum quinolone antibacterial agents against multi-drug resistant bacterial infections. NA has only modest activity against Gram-negative bacteria and low oral absorption, therefore a suitable candidate for treatment of systemic infections (UTIs) is required. Since the original discovery of NA, a series of quinolones, which are referred to as the old quinolones, have been developed leading to the first new quinolone, NFLX, with moderate improvements in over all properties starting in 1962 through and continuing throughout the 1970's. Especially, the drug design for pipemidic acid (PPA) indicated one of the important breakthroughs that lead to NFLX. The introduction of a piperazinyl group, which ia a basic moiety at the C7-position of the quinolone nuclei, improved activity against Gram-negative organisms broadening the spectrum to include Pseudomonas aeruginosa. PPA also showed soem activity against Gram-positive bac teria. The basic piperazine ring, which can form the zwitterionic natrure with the carboxylic acid at the C3-position, has subsequently been shown to increase the ability of the drugs to penetrate the bacterial cells resulting in enhanced activity. Further, the zwitterionic forms resulted in significant tissue penetration in the pharmacokinetics. On the other hand, the first compound with a fluorine atom at the C6-position of the related quinolone scaffold was flumequine and the compound indicated that activity against Gram-positive bacteria could be improved in the old quinolones. The addition of a flourine atom at the C6-position is essential for the inhibition of target enzymes. The results show the poten antibacterial activity and the penetration of the quinolone molecule into the bacterial cells and human tissue. The real breakthrough came with the combination of these two features in NFLX, a 6-fluorinated quinolone having a piperazinyl group at the C7-position, NFLX features significant differences from the old quinolones in the activities and pharmacokinetics in humans, resulting in high clinical efficacy in the treatment of many kinds of infections including RTIs.Consequently, those great discoveries are rapidly superseded by even better compounds and NFLX proved to be just the beginning of a highly successful period of research into the modifications of the new quinolone antibacterials. Simce the chemical structure and important features of NFLX had become apparent in 1978, many compounds were patented in the next three years, several of which reached the market. Among the drugs, ofloxacin (OFLX) and ciprofloxacin (CPFX) are recognized as superior in several respects to the oral beta-lactam antibiotics as an antibacterial agent. With a focus on OFLX and CPFX, numerous research groups entered the antibacterial therapeutic field, triggering intense competition in the search to find newer, more effective quinolones. After NFLX was introduced in the market, while resulting by the end of today, eleven kinds of other new quinolones launched in Japan. They are enoxacin (ENX), OFLX, CPFX, lomefloxacin (LFLX), fleroxacin (FRLX), tosufloxacin (TFLX), levofloxacin (LVFX), sparfloxacin (SPFX), gatifloxacin (GFLX), prulifloxacin (PULX) and also pazufloxacin (PZFX). The advantages of these compounds, e.g., LVFX, SPFX and GFLX, are that their spectrum includes Gram-positive bacteria species as well as Gram-negative bacteria and they improve bioavailability results when a daily dose is administered for systemic infections including RTIs. However, unexpected adverse reactions, such as the CNS reaction, the drug-drug interaction, phototoxicity, hepatotoxicity and cardiotoxicity such as the QTc interval prolongation of ECG, have been reported in the clinical evaluations or the post-marketing surveillance of several new quinolones. Moreover, the adverse reactions of arthropathy (the joint toxicity) predicated from studies in juvenile animals have never materialized in clinical use. Therefore, no drugs other than NFLX have yet been approved for pediatric use. Fortunately, the newer quinolones are being developed and tested to reduce these adverse reactions on the basis of recent studies. On the other hand, multi-drug resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphycolocci (MRCNS), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomycin-resistant enterococci (VRE) have been a serious problem in the medical community. Recently, the new quinolone antibacterials are highly successful class of antibacterial therapeutic field, however, the increased isolation of quinolone-resistant bacteria above them has become a normal outcome. These problems of multi-drug resistance have been the driving force for the development of newer quinolones. The next gereration of quinolone antibacterial agents will be potent against multi-drug resistant bacteria, such as MRSA, and provide a lower rate of emergence in resistance. Further, they should have favorable safety profiles to reduce the adverse reactions. The future of quinolones as the ultimate in pharmaceuticals must be handled cautiously if they are to realize their potential in the medical community.     

Fluorinated quinolones

Quinolones, chemically related to nalidixic acid, have a strong and rapid bactericidal action against Gram-negative bacteria, includingPs. aeruginosa, someMycobacteria, Legionella andStaphylococci. Streptococci and anaerobic bacteria are usually less sensitive. The quinolones exert their bactericidal action through inhibition of the enzyme DNA gyrase. Quinolones are absorbed for 50–100% from the gastro-intestinal tract, their volume of distribution is generally high (2 l/kg) and high concentrations are reached in almost all organs. The elimination half-lives range from 4 to 14 h. The efficacy of quinolones in urinary tract infections has been shown in many studies. They also seem to be effective in many serious infections. In animal studies their efficacy was generally equal or superior to aminoglycosides. Until now only mild and infrequent side effects have been reported.     

某教学医院肛肠疾病术后感染的病原菌特征及其耐药性分析

目的 了解肛肠疾病术后感染的病原菌分布和耐药性特征，为术后细菌性感染的诊断与治疗提供预防措施。方法 收集2016-2018年肛肠科手术患者的临床资料，分析肛肠疾病术后感染的病原菌分布特征和耐药性；应用SPSS 18.0软件进行数据分析。结果 在2714例肛肠疾病手术患者中，186例发生术后感染(6.85%)，其中痔疮92例、肛周脓肿57例、肛裂18例、肛瘘15例、肛乳头肥大3例和直肠息肉1例。从切口部位组织或分泌物中分离194株病原菌，其中革兰阴性菌121株(62.37%)，革兰阳性菌68株(35.05%)和真菌5株(2.58%)。不同肛肠疾病术后感染的病原菌种类和分离率存在较大差异。大肠埃希菌等革兰阴性菌对阿米卡星敏感，对头孢吡肟和氨苄西林/舒巴坦较敏感，对左氧氟沙星耐药率较低，对第一、二代头孢类菌素和第二代喹诺酮类抗菌药物均存在较高耐药性，但未发现亚胺培南耐药株。耐3种以上抗菌药物的革兰阴性菌47株，占革兰阴性菌38.8%。表皮葡萄球菌和金黄色葡萄球菌对利福平敏感；粪肠球菌对利福平和利奈唑胺较敏感；表皮葡萄球菌等革兰阳性菌对氨基糖苷类、喹诺酮类和青霉素类抗菌药物均有较高的耐药性，但未发现万古霉素耐药株以及利奈唑胺耐药的表皮葡萄球菌和金黄色葡萄球菌。耐3种以上抗菌药物的革兰阳性菌22株，占革兰阳性菌32.4%。 结论 肛肠疾病术后感染的病原菌主要为革兰阴性菌，临床应根据病原菌分布特征和耐药性分析，采取积极有效的针对性干预措施，降低肛肠疾病术后感染率和耐药菌的产生。     

Penetrability of ofloxacin into cultured epithelial cells and macrophages

It is well known that the penetration of drugs into host cells is the minimal requirement to exhibit their efficacy against infections with intracellular bacteria. Thus the penetrability of new quinolones including ofloxacin, norfloxacin and ciprofloxacin was evaluated by comparing their intracellular and extracellular activities by the use of cell infection systems in vitro. It was evidenced that the new quinolones tested were penetrable into both epithelial cells and macrophages, however, ofloxacin was more penetrable than norfloxacin and ciprofloxacin into both types of cells which serve the nest for proliferation of intracellular bacteria.