Azithromycin的体外抗菌作用

测定ａｚｉｔｈｒｏｍｙｉｎ（ＡＺＭ）体外抗菌作用，以红霉素（ｅｒｙｔｈｒｏｍｙｃｉｎ，ＥＭ）为对照，并与其它几种大环内酯类抗生素进行了比较，结果表明国产ＡＺＭ对ＥＭ敏感的革兰氏阳性菌的抗菌作用与ＥＭ相似，ＭＩＣ９０在０．５～４．０ｍｇ／Ｌ范围内；对淋病奈瑟氏菌及流感嗜血杆菌的ＭＩＣ９０均为２ｍｇ／Ｌ，为ＥＭ的１／４；对大肠菌和肺炎克雷伯氏菌抗茵作用则明显优于ＥＭ。本品对金葡球菌无杀菌作用，浓度为０．５及０．２５ｍｇ／Ｌ时，对化脓性链球菌及肺炎球菌表现出较强的杀菌作用，并明显优于ＥＭ。

国产与进口azithromycin随机对照试验的临床评价

为评价国产ａｚｉｔｈｒｏｍｙｃｉｎ（ＡＺＭ）在临床治疗急性细菌性感染病人的有效性与安全性，我们以进口ＡＺＭ为对照药，进行随机对照试验治疗细菌性感染２００例。国产与进口ＡＺＭ组各１００例，治疗呼吸系统和皮肤软组织感染均为每日１次，首次５００ｍｇ，以后每次２５０ｍｇ，疗程７ｄ，治疗淋病均为单次口服１ｇ即可。两组痊愈率分别为８０．０％及８４．０％，有效率分别为９３．０％及９１．０％，细菌清除率分别为９３．３％及９２．１％，不良反应发生率分别为７％及６％，以上结果经统计学处理无显著性差异。国产ＡＺＭ临床疗效肯定，使用安全、方便。

Azithromycin的体内抗菌作用研究

口服ａｚｉｔｈｒｏｍｙｃｉｎ对金葡球菌、肺炎球菌、化脓性链球菌各２株感染小鼠的ＥＤ５０值分别为５１．４０和５８．７４ｍｇ／ｋｇ、２０．４０和２８．７４ｍｇ／ｋｇ、２０．９０和２１．７４ｍｇ／ｋｇ，比对照药红霉素的ＥＤ５０（１０１；４２和１０６．８４ｍｇ／ｋｇ，１０４．１２和１６５．７９ｍｇ／ｋｇ，４３．７１和４３．４８ｍｇ／ｋｇ）低，两药ＥＤ５０值经统计学处理有显著性差异（Ｐ＜０．０１）。

azithromycin的临床评价

口服国产ａｚｉｔｈｒｏｍｙｃｉｎ治疗细菌性感染１１０例，评价其疗效和安全性。治疗结果有效率为９３．６％（１０３／１１０），细菌清除率为９１．４％（９６／１０５）。不良反应发生率为５．４％（６／１１０），症状轻微，以胃肠道反应为主，个别患者出现一过性实验室异常。同时对国产ａｚｉｔｈｒｏｍｙｃｉｎ与进口品治疗呼吸道感染的疗效和安全性进行了随机对照观察，分别治疗５２例和５０例。

Azithromycin对临床常见致病菌的体外抗菌作用研究

研究了国产ａｚｉｔｈｒｏｍｙｃｉｎ及红霉素等５种大环内酯类抗生素对５２１株临床分离致病菌的体外抗菌作用。结果表明：ａｚｉｔｈｒｏｍｙｃｉｎ对敏感的金葡球菌、肺炎链球菌、化脓性链球菌、淋球菌、嗜血流感杆菌、粪链球菌及脆弱拟杆菌等均具有较好的抗菌作用（ＭＩＣ５０＜０．０１６～０．５ｍｇ／Ｌ）。对敏感的金葡球菌ＭＩＣ５０与ＭＩＣ９０分别为０．０１６与０．０３１ｍｇ／Ｌ，对脆弱拟杆菌ＭＩＣ５０与ＭＩＣ９０分别为０．０１６与０．１２５ｍｇ／Ｌ。ａｚｉｔｈｒｏｍｙｃｉｎ对所测试的多数致病菌的抗菌作用与红霉素相似或稍强，本品与红霉素有交叉耐药性。

阿齐霉素治疗弓形虫病初步研究

近年来试用阿齐霉素(Azithromycin、Sumamed克罗地亚PLIVA药厂出品)治疗小鼠弓形虫感染及临床确诊弓形虫病例,均取得一定疗效。 1 小鼠感染人源型弓形虫KS强毒株,从接种0.5×10~3—1.0×10~5后2h后每日一次喂服阿齐霉素100—200mg/kg×5—10d,虽仍有类似对照组较轻的发病,并晚死亡2d左右,但腹液稀薄、澄清、镜下虫体极少,比对照组减少95％以上,油镜所见虫体成倍胀大或裂解,泡浆凝集成网状,核浅染,且以此腹液接种健康鼠,发病不明显,50d时取全部鼠脑,用淋巴细胞分离液法,在三层分离液层作多张厚涂片,姬氏染色均未查见弓形虫包囊。 2 临床弓形虫病例治疗 试治8例有全身性症状、脑炎、伴肝脾肿大或淋巴结肿大及多次畸胎史,并经IHA、ELISA-IgG、IgM。

Azithromycin临床药物动力学研究

对１０名健康志愿者口服ａｚｉｔｈｒｏｍｙｃｉｎ的药物动力学研究以及其干糖粉的相对生物利用度测定结果显示：空腹口服ａｚｉｔｈｒｏｍｙｃｉｎ单剂５００ｍｇ后，其体内过程符合二室模型，其消除半衰期为５０．３９±８．８７ｈ；高峰血浓度为０．４０３±０．２９９ｍｇ／Ｌ；达峰时间为２．６４±１．２６ｈ，ＡＵＣ为６．３９±１．８１ｈｍｇ／Ｌ。１４４ｈ累积尿排出率为１１．５２％±２．７０％。干糖粉与胶囊比较的相对生物利用度为１１０．６％。根据其药物动力学参数和抗微生物活性。

Azithromycin胶囊剂与罗红霉素片剂随机对照治疗急性感染比较

用国产ａｚｉｔｈｒｏｍｙｃｉｎ（ＡＺＭ）和进口罗红霉素作随机对照，ＡＺＭ５００ｍｇ每日１次，疗程３ｄ。非淋球菌性尿道炎１ｇ单剂量；进口罗红霉素１５０ｍｇ每日２次，疗程７ｄ。两组各６１例（呼吸道感染各４１例，非淋球菌性尿道炎各２０例）。试验组和对照组的痊愈率和有效率分别为７７．０５％、９３．４４％；６８．８５％、９０．１６％（Ｐ＞０．０５）。开放试验４２例，呼吸系统感染２５例，皮肤软组织感染１７例，痊愈率和有效率分别为７３．８１％、９２．８６％。细菌的阴转率和消除率分别为９１．２３％、９０．４８％；８６．４４％、８６．１５％（Ｐ＞０．０５）。试验组和对照组细菌有效率分别为９２．９８％、９１．５２％（Ｐ＞０．０５）。试验组和对照组不良反应发生率都为３．２８％，不良反应相同，开放组为２．３８％。提示ＡＺＭ和进口罗红霉素疗效满意，不良反应少，但ＡＺＭ总用药量少、疗程短为其一大优点。

5种抗菌药物对厌氧菌的体外抗菌活性研究

测定了罗红霉素、ａｚｉｔｈｒｏｍｙｃｉｎ、头孢西丁、托舒沙星对６０株厌氧菌的体外抗菌活性，并同甲硝唑比较，发现托舒沙星对厌氧菌的体外抗菌活性最好，ＭＩＣ_（５０）和ＭＩＣ_（９０）为０．１２５和２ｍｇ／Ｌ优于甲硝唑（０．２５和１６ｍｇ／Ｌ）；罗红霉素（０．５、１６ｍｇ／Ｌ）与甲硝唑相似，ａｚｉｔｈｒｏｍｙｃｉｎ、头孢西丁的体外抗菌活性比甲硝唑略差，ＭＩＣ_（５０）和ＭＩＣ_（９０）分别为４和３２、２和３２ｍｇ／Ｌ，它们对脆弱拟杆菌的体外抗菌活性优于对其它拟杆菌的体外抗菌活性，对短真杆菌、变形链球菌、普氏消化链球菌等也具有较好的体外抗菌活性。

第一个15元大环内酯类抗生素Azithromycin

尽管大环内酯类抗生素的重要代表红霉素(EM)在临床上的应用已有30多年了,但是由于EM对军团菌病、弯曲杆菌腹泻,枝原体及衣原体感染与性病等的有效治疗作用,近年来又再次引起了人们的极大重视。然而EM本身具有的不良之处如抗菌谱较窄、口服吸收不规则、胃肠道与肝功能方面的不良反应等又限制了EM的应用。鉴此,欧、美。

Azithromycin及其相关化合物的分析

azithromycin(CP-62993,XZ-450,AM)是具有15元的氮杂内酯(azalactone)环的半合成大环内酯类抗生素。化学结构上系在红霉素A内酯环的9a位内插一个含有取代甲基的氮原子,成为氮杂类(azalids)化合物。修饰后的产物即azithromycin,较母体化合物红霉素扩大了抗菌谱,提高了抗菌活力和对酸性环境的稳定性。口服后生物利用度高,半衰期较长,具有更高的组织浓度。1993年已收入美国药典Ⅹ Ⅹ Ⅱ版第8补编内。本文介绍AM的有关化学、酸稳定性研究。

阿齐霉素的临床药理研究与应用

阿齐霉素(Azithromycin,AZM)是一个新的红霉素衍生物,也是第一个氮环内酯抗生素.该药80年代初由美国Pfizer公司研制成功.与临床应用广泛的大环内酯类抗生素红霉素相比,它具有以下优越性:①良好的药物动力学特性:单次po后吸收快,靶组织浓度高,持续时间长;②广谱的抗性传播疾病(STD)病原体活性;③不良反应较轻微,发生率低;④无重要的临床药物相互作用,老年患者、轻中度肾功能不全患者无需调整剂量;⑤简单易行的治疗方案,明显提高病人坚持服药治疗的顺应性.国外许多关于AZM的药物动力学研究和临床评价表明,该药在临床应用上有很大潜力,正得到不断发展.尤其是lg单剂量AZM能有效治疗沙眼衣原体所致单纯性生殖器感染,对于控制沙眼衣原体感染有十分重要的意义,并且,AZM有可能成为一种重要的治疗STD的药物.本文就其近年来国外的临床药理研究和应用作综述如下:

Development of a New Azithromycin Glutamate for Parenteral Preparation, the Toxicity in Sprague-Dawley Rats and Pharmacokinetics in Human Healthy Volunteers

Aim In order to improve the solubility of azithromycin, the objectives of the present study were to screen an appropriate salt for azithromycin by comparing acute hepatic and renal toxicities in animals, and study the pharmacokinetics of final chosen azithromycin salt. Methods Various salts of azithromycin, such as glutamate, citrate, hydrochloride, sulphate, dihydrogen phosphate, lactobionate, tartrate, and aspartate were given intravenously to Sprague Dawley rats at a dose of 10 mg once daily for 14 consecutive days via tail vein. The acute hepatic and renal indicators were measured before and after administration. A pharmacokinetic study was performed on 12 healthy human volunteers. The subjects were equally divided into two groups by a randomized crossover design. Azithromycin glutamate injection was administered by intravenous infusion or intramuscular injection at a single dose of 500 mg, respectively. Azithromycin concentrations in plasma were determined by microbial inhibition zone assay, and the pharmacokinetic parameters were calculated using a practical pharmacokinetic software 3P87 program. Results Azithromycin glutamate was least toxic to the liver and kidney of the rats, thus being selected as a final salt for parenteral preparation of azithromycin. Pharmacokinetic results showed that the area under the plasma concentration-time curves （AUC0-120h） were 21.47 ± 1.57 h·μg·mL^-1 for intravenous infusion, and 19.36 ± 2.44 h·μg·mL^-1 for intramuscular injection. The absolute bioavailability of intramuscular injection was 92.59%. Conclusion Azithromycin glutamate is suitable for the future clinical application, and its pharmacokinetics is characterized in human volunteers in the present study.

Fluoroquinolone-macrolide combination therapy for chronic bacterial prostatitis： retrospective analysis of pathogen eradication rates, inflammatory findings and sexual dysfunction

We previously demonstrated the safety and efficacy of fluoroquinolone-macrolide combination therapy in category Ⅱ chronic bacterial prostatitis （CBP）. The aim of this study is to retrospectively compare the microbiological and clinical findings of two treatment schemes for CBP based on the combination of azithromycin （500 rag, thrice-weekly） with a once-daily 500- or 750-mg dose of ciprofloxacin （Cipro-500 or Cipro-750 cohort, respectively）. Combined administration of azithromycin （1500 mg week^-1） with ciprofloxacin at the rate of 750 mg day^- 1 for 4 weeks rather than at 500 mg day^- 1 for 6 weeks increased the eradication rates from 62.35% to 77.32% and the total bacteriological success from 71.76% to 85.57%. A significant decrease in pain and voiding signs/symptoms and a significant reduction in inflammatory leukocyte counts and serum prostate-specific antigen （PSA） were sustained throughout an 18-month follow-up period in both groups. Ejaculatory pain, haemospermia and premature ejaculation were significantly attenuated on microbiological eradication in both groups, but the latter subsided more promptly in the Cipro-750 cohort. In total, 59 Cipro-750 patients showed mild-to-severe erectile dysfunction （ED） at baseline, while 22 patients had no ED on microbiological eradication and throughout the follow-up period. In conclusion fluoroquinolone-macrolide therapy resulted in pathogen eradication and CBP symptom attenuation, including pain, voiding disturbances and sexual dysfunction. A once-daily 750-mg dose of ciprofloxacin for 4 weeks showed enhanced eradication rates and lower inflammatory white blood cell counts compared to the 500-mg dose for 6 weeks. Our results are open to further prospective validation.

Azithromycin-containing versus standard triple therapy for Helicobacter pylori eradication:A meta-analysis

AIM： To evaluate whether adding azithromycin to firstline Helicobacter pylori （H pylorl） eradication improved eradication and reduced side effects. METHODS： Eligible articles were identified by searches of electronic databases. We included all randomized trials that compared azithromycin-containing with standard triple-therapy regimens for first-line treatment of H pylori infection. Statistical analysis was performed with Review Manager 5.0.10. Sub-analyses were also performed. RESULTS： We identified 14 randomized trials （1431 patients）. Pooled Hpylori eradication rates were 72.01% （95% CI： 58.09%-85.93%） and 69.78% （95% CI： 66.47%-73.09%） for patients with or without azithromycin by intention-to-treat analysis, and the odds ratio （OR） was 1.17 （95% CI： 0.64-2.14）. The occurrence of side effects differed significantly and was 15.81% （95% CI： 12.50%-19.12%） and 25.20% （95% CI： 21.44%-28.96%） for treatment with or without azithromycin, respectively, and the summary OR was 0.58 （95% CI： 0.41-0.82）. Furthermore, the azithromycin-containing group had a lower occurrence of diarrhea, nausea and taste disturbance. CONCLUSION： Our review suggests that azithromycincontaining triple-therapy regimens could be equally effective in eradication of Hpylori compared with standard first-line triple-therapy regimens.

Prevalence and antimicrobial resistance of non-typhoid Solmonella in military personnel,1988-2013

Objective:To describe the spanning 25 years data for the occurrence, magnitude, and trends regarding antimicrobial resistance of non-typhoidalSalmonella (NTS) isolated from non-immune travelers to Thailand participating in joint military operations.Methods:A total of 355 NTS isolates, obtained from 2052 fecal samples from US soldiers deployed for military maneuvers in Thailand during 1988-2013, were examined for NTS serogroup/serotypes and tested for antimicrobial susceptibility by disk diffusion to these 10 antibiotics:ampicillin, azithromycin (AZM), ciprofloxacin, colistin, gentamicin, kanamycin, nalidixic acid, streptomycin (STR), tetracycline (TET), and trimethoprim/sulfamethoxazole. Identified AZM-resistant NTS isolates were further evaluated for their minimal inhibitory concentration by the E-test method.Results:NTS infections accounted for 17.3％ (355/2052), including 11 serogroups and 50 different serotypes. The most prevalent serogroup wasSalmonella group C2-C3 (35.8％, 127/355) followed by groups B (21.1％, 75/355) and C1 (18.6％, 66/355). Identified serotypes includedSalmonellahadar (n=60),Salmonellarissen (n=45), andSalmonella blockley (n=34). Among the predominate serogroups, antimicrobial resistance was consistently high against TET (76.9％, 273/355) followed by STR (40.8％, 145/355). OneSalmonella senftenberg isolate demonstrated decreased ciprofloxacin susceptibility. Most isolates (94.6％) were resistant to one or more antimicrobials, and the most common multidrug resistance was TET-STR-nalidixic acid (11.5％, 41/355).Conclusions:The prevalence of NTS serotypes and the growing magnitude of antibiotic resistant bacteria isolated from deployed US military in Thailand are documented from 1988-2013. This study demonstrates the antibiotic resistance profiles, highlighting the effectiveness of AZM that is a first-line treatment for travelers to Southeast Asia. AZM-resistant NTS isolates are periodically observed over a 25-year period. Hence, the ongoing surveillance and prevalence efforts are required to monitor NTS resistant strains causing further treatment failure.

Azithromycin in one week quadruple therapy for H pylori eradication in Iran

AIM： To investigate eradication rates, patient compliance and tolerability of a 1-wk Azithromycin-based quadruple therapy versus the 2-wk conventional therapy. METHODS： A total of 129 Hpylori-positive patients were randomized to either omeprazole 20 mg, bismuth subcitrate 240 mg, azithromycin 250 mg, and metronidazole 500 mg, all twice daily for 1-wk （B-OAzM） or omeprazole 20 mg, bismuth subcitrate 240 mg, amoxicillin lg, and metronidazole 500 mg all twice daily for 2-wk （B-OAM）. Hpylori infection was defined at entry by histology and rapid urease test and cure of infection was determined by negative urea breath test. RESULTS： Hpylori eradication rates produced by B-OAzM and B-OAM were 74.1% and 70.4% respectively based on an intention to treat analysis, and 78.1% versus 75.7% respectively based on a per-protocol analysis. The incidence of poor compliance was lower, although not significantly so, in patients randomized to B-OAzM than for B-OAM （3.5% versus 4.3%） but intolerability was similar in the two groups （ 35% versus 33.3%）. CONCLUSION： 1-wk azithromycin based quadruple regimen achieves an Hpylori eradication rate comparable to that of standard 2-wk quadruple therapy, and is associated with comparable patient compliance and complications.

Efficacy of Moxifloxacin against Mycobacterium abscessus in Zebrafish Model in vivo

Objective Moxifloxacin(MFX)shows good in vitro activity against Mycobacterium abscessus and can be a possible antibiotic therapy to treat M.abscessus infection;however,other studies have shown a lower or no activity.We aimed to evaluate MFX activity against M.abscessus using zebrafish(ZF)model in vivo.Methods A formulation of M.abscessus labeled with CM-Dil was micro-injected into ZF.Survival curves were determined by recording dead ZF every day.ZF were lysed,and colony-forming units(CFUs)were enumerated.Bacteria dissemination and fluorescence intensity in ZF were analyzed.Inhibition rates of MFX and azithromycin(AZM,positive control)were determined and compared.Results Significantly increased survival rate was observed with different AZM concentrations.However,increasing MFX concentration did not result in a significant decrease in ZF survival curve.No significant differences in bacterial burdens by CFU loads were observed between AZM and MFX groups at various concentrations.Bacterial fluorescence intensity in ZF was significantly correlated with AZM concentration.However,with increasing MFX concentration,fluorescence intensity decreased slightly when observed under fluorescence microscope.Transferring rates at various concentrations were comparable between the MFX and AZM groups,with no significant difference.Conclusion MFX showed limited efficacy against M.abscessus in vivo using ZF model.Its activity in vivo needs to be confirmed.

Azithromycin in a triple therapy for H.pylori eradication in active duodenal ulcer

AIM:To assess and compare the efficacy and safety of two triple regimes:A)metronidazole,amoxicillin and omeprazole, which is still widely used in Russia,and B)azithromycin, amoxicillin and omeprazole in healing active duodenal ulcer and H.pylori eradication. METHODS:100 patients with active duodenal ulcer were included in the open,multicentre,randomized study with comparative groups.Patients were randomly assigned to one of the following one-week triple regimes:A) metronidazole 500 mg bid,amoxicillin I g bid and omeprazole 20 mg bid(OAM,n=50)and B)azithromycin 1 god for the first 3 days(total dose 3 g),amoxicillin 1 g bid and omeprazole 20 mg bid(OAA,n=50).Omeprazole 20 mg od was given after the eradication course as a monotherapy for three weeks.The control endoscopy was performed 8 weeks after the entry.H.pyloriinfection was determined in the entry of the study and four weeks after the cessation of treatment by means of histology and CLO-test. RESULTS:97 patients completed the study according to the protocol(1 patient of the OAM group did not come to the control endoscopy,2 patients of the OAA group stopped the treatment because of mild allergic urticaria).Duodenal ulcers were healed in 48 patients of the OAM group(96 %, C190.5-100 %)and in 46 patients of the OAA group(92 %, CI 89.5-94.5 %)(p=ns).H.pyloHinfection was eradicated in 15 out of 50 patients with OAM(30 %,CI 17-43 %)and in 36 out of 50 patients treated with OAA(72 %;CI 59-85 %) (P<0.001)-ITT analysis.CONCLUSION: The triple therapy with omeprazole, amoxicillin and metronidazole failed to eradicate H.pylori'vc\ the majority of patients, which is an essential argument to withdraw this regimen out of the national recommendations. Macrolide with amoxicillin are preferable to achieve higher eradication rates. Azithromycin (1 g od for the first 3 days) can be considered as a successful component of the triple PPI-based regimen.

Synthesis of novel 15-membered macrolide derivatives

In order to develop new antibiotics effective against resistant bacteria,a series of novel 15-membered macrolide derivatives were designed and synthesized by the modification of hydroxyl groups at C-11,C-12 and C-4＂ positions.Their structures were confirmed by MS,IR,^1H NMR or ^13C NMR.