红霉素环11,12-碳酸酯于小鼠体内的抗菌活性研究

目的 评价红霉素环11，12-碳酸酯的体内抗菌活性。方法 采用小鼠腹腔感染模型，观察红霉素环11，12-碳酸酯口服对临床分离的金葡菌、化脓链球菌、肺炎链球菌感染小鼠的体内疗效，并与罗红霉素、红霉素进行比较。结果 红霉素环11，12-碳酸酯口服对金葡菌15、金葡菌91—29、化脓链球菌94—3、化脓链球菌556、肺炎链球菌9—9、肺炎链球菌9—5感染小鼠的ED50值分别为38．84、37．08、8．62、9．15、12．76、31，42mg／kg，抗菌活性比红霉素强2～8倍，与罗红霉素相近。结论 红霉素环11，12-碳酸酯对金葡菌、化脓链球菌和肺炎链球菌感染小鼠均有较强的保护作用，抗菌活性明显优于红霉素，与罗红霉素相近。     

阿奇霉素4″-取代亚苄肼基甲酸酯衍生物的合成和抗菌活性

以阿奇霉素11，12-环硼酸酯为原料．设计并合成了18个阿奇霉素4″-取代亚苄肼基甲酸酯及4″-取代亚苄肼基甲酸酯．11，12-环碳酸酯衍生物。体外抗菌活性试验结果表明，所得化合物对受试革兰阳性菌如金黄色葡萄球菌、表皮葡萄球菌、白色葡萄球菌和肺炎双球菌抗菌活性良好，部分化合物对丙型链球菌、革兰阴性菌如鲍氏志贺氏菌和普通变形杆菌也有较强的抗菌活性。     

环酯红霉素对近5年临床分离菌株的体外敏感性研究

目的通过比较近五年临床分离菌株对多种抗菌药物的药物敏感性及耐药性研究,了解环酯红霉素的体外抗菌活性。方法利用琼脂平板稀释法对临床分离220株细菌进行药敏性分析。结果药物敏感性实验表明肺炎链球菌、化脓链球菌、金黄色葡萄球菌、表皮葡萄球菌和流感嗜血菌对环酯红霉素的耐药率分别为35.0%、55.0%、35.0%、36.7%和70.0%。肺炎链球菌、化脓链球菌、金黄色葡萄球菌、表皮葡萄球菌和流感嗜血菌对环酯红霉素的MIC50和MIC90分别为1、1、32、0.5、64μg/mL和32、8、256、32、128μg/mL。结论经SPSS17.0统计分析后,发现临床分离菌株对环酯红霉素和阿奇霉素的耐药率表明两者的抗菌活性相当,不存在统计学差异(P>0.05)。     

进口注射用克拉霉素与国产注射用乳糖酸红霉素体内外抗菌活性的比较

目的 研究进口注射用克拉霉素与国产注射用乳糖酸红霉素对四川地区临床分离致病菌的体内、外抗菌活性.方法 测定260株临床分离致病菌的最低抑菌浓度(MIC)、最低杀菌浓度(MBC),采用活菌计数法绘制杀菌曲线,并观察细菌接种量、培养基pH和血清蛋白含量对体外抗菌活性的影响,采用小鼠100%mLD菌量测定并计算ED_(50)及95%可信限来观察注射用克拉霉素的体内抗菌活性.结果 进口注射用克拉霉素MBC的浓度较其MIC的浓度高4～16倍,为抑菌剂;当接种菌量由5×10~3CFU·mL~(-1)增至5×10~7CFU·mL~(-1)时,进口注射用克拉霉素的MIC值增加2～4倍.pH偏碱,抗菌作用增强,尤以pH8～9时,抗菌作用明显增强,血清浓度75%时,抗菌作用有所减弱.进口注射用克拉霉素静脉给药,对敏感的金黄色葡萄球菌、化脓性链球菌和流感嗜血杆菌感染的小鼠具有保护作用,优于国产注射用乳糖酸红霉素.结论 进口注射用克拉霉素比国产注射用乳糖酸红霉素具有更好的抗菌活性,可供临床参考.     

罗红霉素体外抗菌作用的研究

本文研究了国产罗红霉素对３９１株临床分离菌的体外抗菌作用。研究结果表明，国产罗红霉素的抗菌作用与进口罗红霉素一致。罗红霉素对红霉素敏感的金葡球菌、表葡球菌、化脓链球菌、肺炎链球菌、粪链球菌、流感嗜血杆菌、淋病奈瑟氏球菌及厌氧菌有较好的抗菌作用，其ＭＩＣ５０分别为０．１２５、０．１２５、１、１、４、４、０．１２５、０．０６２ｍｇ／Ｌ，细菌接种量对国产罗红霉素的体外抗菌作用因菌种不同而异，金葡球菌和表     

国产克林霉素磷酸酯体外抗菌作用研究

国产、进口克林霉素磷酸酯与盐酸克林霉素对革兰氏阳性菌和阴性菌及厌氧菌具有相似的体外抗菌活性，克林霉素磷酸酯经碱性磷酸酯酶水解后，对金葡球菌、表葡球菌抗菌活性与红霉素及氯唑西林相似，ＭＩＣ＿（５０）分别为０．０６２和０．１２５ｍｇ／Ｌ，低于盐酸林可霉素。对一些红霉素耐药的金葡球菌、表葡球菌也有一定抗菌活性，最低ＭＩＣ＿（５０）分别为０．０６２和０．５ｍｇ／Ｌ，对肺炎链球菌、化脓性链球菌具有较好的抗菌活性，ＭＩＣ＿（５０）分别为０．０３１和０．０６２ｍｇ／Ｌ，对革兰氏阳性、阴性厌氧菌具有较强的抗菌活性，ＭＩＣ＿（５０）分别为０．０６２～０．５ｍｇ／Ｌ，ＭＩＣ＿（９０）为０．２５～４ｍｇ／Ｌ。结果表明，克林霉素磷酸酯对金葡球菌、表葡球菌、肺炎链球菌、化脓链球菌ＭＢＣ＿（５０）较其ＭＩＣ＿（５０）高１～４倍，其它结果显示克林霉素磷酸酯不受ｐＨ或接种量影响。     

阿奇霉素衍生物的合成及抗菌活性Ⅱ.4"-取代酰基肼基甲酸酯

分别以阿奇霉素11,12-环硼酸酯和阿奇霉素为原料,设计并合成了22个阿奇霉素4"-取代酰基肼基甲酸酯及4"-取代酰基肼基甲酸酯-11,12-环碳酸酯衍生物.体外抗菌活性试验结果表明,所得大部分化合物对受试革兰阳性金黄色葡萄球菌和肠球菌抗菌活性良好,部分化合物对革兰阳性表皮葡萄球菌、丙型链球菌和革兰阴性福氏志贺菌也有较强的抗菌活性.     

阿奇霉素4"-取代亚苄肼基甲酸酯衍生物的合成和抗菌活性

以阿奇霉素11,12-环硼酸酯为原料,设计并合成了18个阿奇霉素4'-取代亚苄肼基甲酸酯及4'-取代亚苄肼基甲酸酯-11,12-环碳酸酯衍生物。体外抗菌活性试验结果表明,所得化合物对受试革兰阳性菌如金黄色葡萄球菌、表皮葡萄球菌、白色葡萄球菌和肺炎双球菌抗菌活性良好,部分化合物对丙型链球菌、革兰阴性菌如鲍氏志贺氏菌和普通变形杆菌也有较强的抗菌活性。     

阿奇霉素衍生物的合成和抗菌活性研究.Ⅲ.4"-取代亚乙基肼基甲酸酯

以阿奇霉素11,12-环硼酸酯为原料,设计并合成了17个阿奇霉素4"-取代亚乙基肼基甲酸酯及4"-取代亚乙基肼基甲酸酯-11,12-环碳酸酯衍生物.体外抗菌活性试验结果表明,目标化合物对受试表皮葡萄球菌、白色葡萄球菌、肺炎双球菌和丙型链球菌等革兰阳性菌,以及福氏志贺菌等革兰阴性菌抗菌活性良好,部分化合物对革兰阳性金黄色葡萄球菌和肠球菌也有较强的抗菌活性.     

阿奇霉素衍生物的合成和抗菌活性研究.Ⅳ.4"-取代杂芳环亚甲基肼基甲酸酯

以阿奇霉素11,12-环硼酸酯为原料,设计并合成了13个阿奇霉素4"-取代杂芳环亚甲基肼基甲酸酯及4"-取代杂芳环亚甲基肼基甲酸酯-11,12-环碳酸酯衍生物.体外抗菌活性试验结果表明,目标化合物对金黄色葡萄球菌、表皮葡萄球菌、白色葡萄球菌、肺炎双球菌和丙型链球菌等革兰阳性菌,以及福氏志贺菌等革兰阴性菌抗菌活性良好.     

L-aspartate of erythromycin A cyclic 11,12-carbonate, a new semisynthetic erythromycin derivative.

Erythromycin A cyclic 11,12-carbonate, a compound with high antibacterial activity, forms with L-aspartic acid a salt possessing valuable properties as a potential chemotherapeutic agent. The L-aspartate of erythromycin A cyclic 11,12-carbonate exhibits strong anti-bacterial activity, especially against Gram-positive bacteria and shows low toxicity. The serum and the lung tissue levels of the discussed salt after a single dose administration to a rat were measured in comparison with those of erythromycin, its L-aspartate, erythromycin cyclic 11,12-carbonate and its L-glutamate. The new erythromycin derivative showed definitely superior characteristics to those of the other substances tested. The activity of the L-aspartate of erythromycin A cyclic 11,12-carbonate in chemotherapy of experimental staphylococcal infection and experimental pneumococcal bronchopneumonia in mice is superior to that of the parent carbonate and erythromycin itself.     

Comparative antimicrobial activity and post-antibiotic effect of azithromycin, clarithromycin and roxithromycin against some respiratory pathogens

Recent macrolide derivatives, roxithromycin, azithromycin and clarithromycin show more favourable pharmacokinetic characteristics in comparison to old ones and some differences in antibacterial activity. With the aim of improving our understanding of some aspects of their action against respiratory pathogens, we determined the MICs and MBCs of Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Moraxella catarrhalis and Haemophilus influenzae. Azithromycin was the most active agent against Haemophilus influenzae and Moraxella catarrhalis, while clarithromycin was more active against Streptococcus pneumoniae, Streptococcus pyogenes and Staphylococcus aureus with MICs similar to those of erythromycin. The bactericidal activity of all tested derivatives was weak against Staphylococcus aureus (MBC/MIC ratio approximately 16) and against Moraxella catarrhalis (MBC/MIC ratio, 8-16), but good against Staphylococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae (MBC/MIC ratio, 2-4). The determination of killing curves in the presence of 2 MIC and 10 MIC of azithromycin, clarithromycin and roxithromycin confirmed their weak bactericidal activity against Staphylococcus aureus and Moraxella catarrhalis as well as their effective activity against Streptococcus pyogenes and Streptococcus pneumoniae. Azithromycin showed the highest bactericidal activity against Haemophilus influenzae. As expected, the three derivatives produced a quite prolonged PAE when exposed to 5 MIC for 1 h, ranging between 2-4 h. The bactericidal activity and the prolonged PAE of new macrolides for the most common respiratory pathogens should assure a good clinical activity in respiratory infections including those sustained by Haemophilus influenzae, which is less susceptible to erythromycin and other old macrolides.     

2008-2014年武汉地区32家医院大环内酯类抗菌药物应用分析

目的：通过调查分析2008-2014年武汉地区32家医院大环内酯类抗菌药物使用现状,为其合理使用提出建议。方法：通过对阿奇霉素、克拉霉素、地红霉素、罗红霉素、红霉素、环酯红霉素、依托红霉素、交沙霉素、麦迪霉素、乙酰螺旋霉素、吉他霉素、琥乙红霉素、乙酰麦迪霉素、乙酰吉他霉素等大环内酯类抗菌药物的用药量、用药金额、限定日计量（DDD）、用药频度（DDDs）、日均费用（DDC）、排序比等指标进行分析,了解其临床使用现状并预测未来使用趋势。结果：用药量排名前5的药物用药量之和超过整体用量的80%,分别为阿奇霉素、克拉霉素、地红霉素、罗红霉素及红霉素。14个品种中,除克拉霉素和麦迪霉素用药量逐年增长以外,其余12个品种使用量均有不同程度下降。结论：尽管抗菌药物使用监管政策在短时间内起到限制大环内酯类抗菌药物用量的作用,但仍需继续加强监管,以防出现滥用现象。     

Review of macrolides and ketolides: focus on respiratory tract infections

The first macrolide, erythromycin A, demonstrated broad-spectrum antimicrobial activity and was used primarily for respiratory and skin and soft tissue infections. Newer 14-, 15- and 16-membered ring macrolides such as clarithromycin and the azalide, azithromycin, have been developed to address the limitations of erythromycin. The main structural component of the macrolides is a large lactone ring that varies in size from 12 to 16 atoms. A new group of 14-membered macrolides known as the ketolides have recently been developed which have a 3-keto in place of the L-cladinose moiety. Macrolides reversibly bind to the 23S rRNA and thus, inhibit protein synthesis by blocking elongation. The ketolides have also been reported to bind to 23S rRNA and their mechanism of action is similar to that of macrolides. Macrolide resistance mechanisms include target site alteration, alteration in antibiotic transport and modification of the antibiotic. The macrolides and ketolides exhibit good activity against gram-positive aerobes and some gram-negative aerobes. Ketolides have excellent activity versus macrolide-resistant Streptococcus spp. Including mefA and ermB producing Streptococcus pneumoniae. The newer macrolides, such as azithromycin and clarithromycin, and the ketolides exhibit greater activity against Haemophilus influenzae than erythromycin. The bioavailability of macrolides ranges from 25 to 85%, with corresponding serum concentrations ranging from 0.4 to 12 mg/L and area under the concentration-time curves from 3 to 115 mg/L x h. Half-lives range from short for erythromycin to medium for clarithromycin, roxithromycin and ketolides, to very long for dirithromycin and azithromycin. All of these agents display large volumes of distribution with excellent uptake into respiratory tissues and fluids relative to serum. The majority of the agents are hepatically metabolised and excretion in the urine is limited, with the exception of clarithromycin. Clinical trials involving the macrolides are available for various respiratory infections. In general, macrolides are the preferred treatment for community-acquired pneumonia and alternative treatment for other respiratory infections. These agents are frequently used in patients with penicillin allergies. The macrolides are well-tolerated agents. Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions: group 1 (e.g. erythromycin) are frequently involved, group 2 (e.g. clarithromycin, roxithromycin) are less commonly involved, whereas drug interactions have not been described for group 3 (e.g. azithromycin, dirithromycin). Few pharmacoeconomic studies involving macrolides are presently available. The ketolides are being developed in an attempt to address the increasingly prevalent problems of macrolide-resistant and multiresistant organisms.     

Advanced-generation macrolides: tissue-directed antibiotics

The azalide antibiotic azithromycin and the newer macrolides, such as clarithromycin, dirithromycin and roxithromycin, can be regarded as 'advanced-generation' macrolides compared with erythromycin, the first macrolide used clinically as an antibiotic. Their pharmacokinetics are characterized by a combination of low serum concentrations, high tissue concentrations and, in the case of azithromycin, an extended tissue elimination half-life. Azithromycin is particularly noted for high and prolonged concentrations at the site of infection. This allows once-daily dosing for 3 days in the treatment of respiratory tract infections, in contrast to longer dosage periods required for erythromycin, clarithromycin, roxithromycin and agents belonging to other classes of antibiotics. The spectrum of activity of the advanced-generation macrolides comprises Gram-positive, atypical and upper respiratory anaerobic pathogens. Azithromycin and the active metabolite of clarithromycin also demonstrate activity against community-acquired Gram-negative organisms, such as Haemophilus influenzae. Advanced-generation macrolides, and in particular azithromycin, are highly concentrated within polymorphonuclear leucocytes, which gravitate by chemotactic mechanisms to sites of infection. Following phagocytosis of the pathogens at the infection site, they are exposed to very high, and sometimes cidal, intracellular concentrations of antibacterial agent. Pharmacodynamic models and susceptibility breakpoints derived from studies with other classes of drugs, such as the beta-lactams and aminoglycosides, do not adequately explain the clinical utility of antibacterial agents that achieve high intracellular concentrations. In the case of azithromycin, attention should focus on tissue pharmacokinetic and pharmacodynamic concepts.     

红霉素环11，12—碳酸酯的合成研究

以红霉素A为原料,与环状碳酸酯一步反应得到了红霉素环11,12－碳酸酯,其体内外抗菌活性均强于母体抗体素－红霉素。由于分子内氢键的存在,使之以9R构型的半缩酮异构体形式存在。     

The in vitro activity of some 14-, 15- and 16- membered macrolides against Staphylococcus spp., Legionella spp., Mycoplasma spp. and Ureaplasma urealyticum.

Erythromycin is a macrolide antimicrobial chemically comprised of a 14-membered lactone ring substituted with a neutral (cladinose) and an amino (desosamine) sugar. Recently, a number of new macrolide molecules have been identified containing either 14-, 15- or 16-membered substituted lactone rings. In this study the authors have determined the in vitro activity of roxithromycin and clarithromycin (both 14-membered macrolides), azithromycin (a 15-membered macrolide or azalide) and midecamycin acetate (a 16-membered macrolide) against clinical isolates of Staphylococcus spp., (including methicillin-susceptible and -resistant isolates), Legionella spp., Mycoplasma spp. and Ureaplasma urealyticum. Minimum inhibitory concentrations of the macrolides for the clinical isolates of Staphylococcus spp. examined were widely distributed. However, midecamycin acetate retained activity against those isolates of Staphylococcus spp. exhibiting inducible resistance to erythromycin and the other macrolides tested. Isolates characterised by constitutive resistance to erythromycin were also resistant to midecamycin acetate. All of the macrolides were very active against Legionella spp., with clarithromycin demonstrating the greatest potency (MIC range: less than or equal to 0.03-0.06 mg/l). Isolates of Mycoplasma pneumoniae and Ureaplasma urealyticum were susceptible to all of the macrolides tested. However, erythromycin, roxithromycin, clarithromycin and azithromycin were poorly active against isolates of Mycoplasma hominis. By contrast, the same isolates were susceptible (MIC range: 0.008-0.12 mg/l) to midecamycin acetate.     

9-（E）-红霉素肟的合成工艺改进

以硫氰酸红霉素为原料,经过肟化和碱化反应制得合成第二代大环内酯类抗生素阿奇霉素、罗红霉素和克拉霉素的中间体9-（E）-红霉素肟,总收率为95.8%。目标化合物结构经MS和1H-NMR谱确证。     

环酯红霉素干混悬剂、胶囊与片剂的生物等效性研究

目的:评价环酯红霉素干混悬剂、胶囊与片剂的生物等效性。方法:18名健康志愿者采用开放、随机、三周期交叉的单中心试验。采用HPLC-MS法测定口服给药后不同时间环酯红霉素的血药浓度。利用DAS 2．0计算药动学参数和进行统计分析。结果:受试者口服750 mg参比制剂环酯红霉素片,受试制剂环酯红霉素干混悬剂和胶囊的C_(max)分别为(1375±s 261)Ixg·L~(-1),(1303土356)μg·L~(-1)和(1307±305)μg·L~(-1);t_(max)分别是(2．4±0．8)h,(2．4±1．0)h和(2．9±0．9)h;4UC_(0～48)分别是(13302±4 369)μg·h·L~(-1),(13596±5519)μg·h·L~(-1)和(13564±4 825)μg·h·L~(-1)。受试制剂的相对生物利用度分别为(102±17)％,(102±15)％。结论:环酯红霉素干混悬剂和胶囊与剂量相同的环酯红霉素片参比制剂具有生物等效性。