氟喹诺酮类药物对肠道致病菌的体外耐药性及交叉耐药

目的 了解氟喹诺酮类药物对肠道致病菌的耐药性及交叉耐药的特点,为临床合理用药提供依据.方法 通过加庆大霉素的沙门志贺菌培养基作粪便培养,筛选出致病菌后经生化及血清学进一步鉴定到种、群或血清型,采用CLSI推荐的Kir-by-Bauer法药敏试验,比较诺氟沙星,环丙沙星,氧氟沙星和左氧氟沙星的耐药性.结果 氟喹诺酮类药物对福氏志贺菌的耐药率最高,对弧菌属的敏感性最好.环丙沙星、氧氟沙星和左氧氟沙星3种药物同时耐药占9.4%,3种药物耐药率有区别又存在交叉耐药.结论 氟喹诺酮类药物仍然是治疗肠道致病菌的较好选择,福氏志贺菌感染可选择左氧氟沙星,由于氟喹诺酮类之间存在交叉耐药,尽量避免选用同类药物.     

喹诺酮类药物的耐药性分析及耐药机制初探

目的探讨喹诺酮类药物耐药情况及耐药机制,为临床合理用药提供依据。方法采用法国生物梅里埃公司生产的VITEK-Ⅱ全自动微生物鉴定药敏仪进行鉴定分析,根据美国临床实验室标准化协会(CLSI)标准判断结果,并查阅文献初探细菌耐药机制。结果共收集到病原菌1829株,其中革兰阴性菌1393株(76.16%),革兰阳性菌436株(23.84%)。革兰阴性菌对喹诺酮类药物的耐药率各不相同,大肠埃希菌和阴沟肠杆菌对喹诺酮类药物的耐药性均较高,对氟罗沙星耐药率分别为46.60%、21.67%,对环丙沙星耐药率分别为49.81%、27.14%,对左旋氧氟沙星耐药率分别为46.56%、20.29%。革兰阳性菌(金黄色葡萄球菌、凝固酶阴性葡萄球菌、粪肠球菌)对喹诺酮类药物均较敏感。结论 3种喹诺酮类药物耐药性排序为环丙沙星>氟罗沙星>左旋氧氟沙星。从耐药机制来看,临床除应做药敏试验外,还应根据药物的药动学(PK)/药效学(PD)参数合理选择药物和剂量。     

革兰阴性杆菌对四种氟喹诺酮药物体外耐药监测

目的了解革兰阴性杆菌(G-)对环丙沙星,左氧氟沙星,氧氟沙星,罗美沙星体外抗菌活性,为临床用药提供依据。方法采用K-B纸片法,对分离出的256株菌株进行耐药性监测,并用标准菌株进行监控,以NCCLS标准进行结果判读。结果大肠埃希菌对4种氟喹诺酮类药物有55%以上的耐药率。除铜绿假单胞菌外革兰阴性杆菌对左氧氟沙星的耐药率均低于其他3种药物,克雷伯菌、铜绿假单胞菌、不动杆菌对环丙沙星耐药率在30.76%～33.33%。结论G-杆菌对氟喹诺酮类药物有交叉耐药现象,医生应不断参考本地区细菌耐药变化,最大限度发挥氟喹诺酮药物的作用。     

JCI认证前后氟喹诺酮类药物利用调查

目的 了解在抗菌药物整治活动和国际医疗卫生机构认证标准(JCI)认证前后医院内氟喹诺酮类用药合理性的改善情况。方法 回顾性调查2009—2013年鲍曼不动杆菌(Ab)、铜绿假单胞菌(Pa)、肺炎克雷伯菌(Kp)和大肠埃希菌(Ec)的耐药率和抗菌药物使用强度,以及住院患者左氧氟沙星的用药合理性及氟喹诺酮类的用药差错。结果 抗革兰氏阴性细菌药物使用强度呈下降趋势。Ab、Kp、Ec对环丙沙星和左氧氟沙星耐药率、Pa对左氧氟沙星的耐药率均持续下降。氟喹诺酮类的使用强度逐年下降,与4种细菌对环丙沙星、左氧氟沙星、哌拉西林钠他唑巴坦钠的耐药率、Pa对头孢他啶、头孢吡肟、亚胺培南和美罗培南的耐药率显著正相关。与左氧氟沙星和莫西沙星不同的是,环丙沙星使用强度与细菌耐药性相关性不强。左氧氟沙星静脉给药与口服使用量的比值显著降低(P<0.05),基于肌酐清除率设计剂量的病历占比明显增加(P<0.05)。97.2%的氟喹诺酮类用药差错被药师前瞻性有效拦截。结论 氟喹诺酮类抗菌药的用药规范性和合理性有明显提升。氟喹诺酮类与其他抗菌药在细菌耐药性方面的影响存在复杂的关系。控制氟喹诺酮类抗菌药的过度使用,可积极影响细菌对其他抗菌药的耐药性,但不同氟喹诺酮类药物对细菌耐药性的影响存在差异。     

喹诺酮类药物对临床一线抗结核药敏感性或耐药性结核分枝杆菌分离菌的体外活性

近年来 ,耐药性结核分枝杆菌临床分离菌不断增加 ,给医生选择抗菌治疗药物造成困难。氟喹诺酮类药物中已有部分 (如氧氟沙星 )用于临床对肺结核的治疗 ,随着一些新的氟喹诺酮类药物的开发 ,这类药物可能在临床抗结核分枝杆菌感染中发挥作用。Ruiz- Serrano等评价了环丙沙星、氧氟沙星、左氧氟沙星、格帕沙星、曲伐沙星和新化合物 gemifloxacin(SB- 2 6 5 80 5 )对临床一线抗结核药 (异烟肼 ,利福平 ,乙胺丁醇 ,链霉素 )敏感性各异的结核分枝杆菌的体外活性。 2 5 0株结核分枝杆菌分离株从收集的临床标本中获得 (1988～ 1999年 ) ,其中 197…     

太原市3家医院喹诺酮类药物1997至2002年的耐药性变迁

目的：分析太原市3家医院临床常见病原菌对喹诺酮类药物的耐药趋势。方法：对太原市3家医院1997至2002年诺氟沙星、环丙沙星的药敏结果和2002年氟洛沙星、洛美沙星、罗帕沙星、氧氟沙星、左氧氟沙星的药敏结果进行分析。药敏试验采用纸片扩散法。结果：太原市3家医院临床常见病原菌6a中对诺氟沙星、环丙沙星耐药总体呈上升趋势，自2001年后趋于平稳，耐药率与用药频度之间呈正相关。在7种喹诺酮类药物中洛美沙星的耐药率最高，左氧氟沙星的耐药率最低，喹诺酮类药物问交叉耐药。结论：病原菌对喹诺酮类药物耐药率的增高与喹诺酮类药物的广泛应用有关；在病原菌对某种喹诺酮类药物不敏感时．应避免使用其他喹诺酮类药物。     

结核分枝杆菌对氟喹诺酮类药物的耐药性研究进展

氟喹诺酮类药物在耐多药结核治疗中的应用日益广泛，但结核分枝杆菌对其耐药性也逐渐增加，特别是当不合理用药时更易发生。因此，研究其耐药机制，加强合理应用以控制耐药性的增长是非常有必要的。本文对氟喹诺酮类药物耐药状况、耐药机制等研究近况作一综述，为临床合理用药提供一定参考。     

531株结核分枝杆菌的药敏分析

目的对结核分枝杆菌的药敏试验结果进行分析,根据敏感率和耐药率情况为临床制定治疗方案和选择用药提供参考依据。方法采用罗氏培养基培养临床标本,药物敏感试验用液体培养基和96孔U型细菌鉴定及药敏试剂板。结果对16种分枝杆菌治疗药物进行药敏测定,其中耐药率最高的是氯法齐明,其次是链霉素,分别是92.7%和39.5%,敏感率最高的是利奈唑胺,敏感度为95%,氟喹诺酮类药物对结核分枝杆菌也有较强的抑菌效果。非结核分枝杆菌药物克拉霉素对结核分枝杆菌也具有较好的抑菌效果。结论本文对531株结核分枝杆菌的药敏试验进行分析,认为对复治的肺结核患者痰培养和药敏试验是必要的,临床用药可以适当考虑选用氟喹诺酮类药物和克拉霉素。     

氟喹诺酮类抗菌药物应用分析

目的:了解氟喹诺酮类抗菌药物使用情况,为合理用药提供依据。方法:对2007—2008年氟喹诺酮类药物使用数量、消耗金额、用药频度(DDDs)和日均费用(DDC)进行统计分析。结果:2007—2008年均是左氧氟沙星针用药频度最高,而2008年氟喹诺酮类抗菌药物销售金额有所下降。结论:近2年内氟喹诺酮类抗菌药物的使用情况基本一致,随着氟喹诺酮类抗菌药物耐药问题的日益严重,应加强临床抗菌药物合理应用的监督管理,以提高临床抗菌药物合理应用水平。     

156例泌尿道感染患者病原菌的分布及其对不同氟喹诺酮类药物的耐药率分析

目的:比较和分析泌尿道感染患者病原菌的分布及其对不同氟喹诺酮类药物的耐药率,为临床合理使用氟喹诺酮类药物提供参考。方法:选取2014年1月—2018年1月间收治的泌尿道感染患者156例资料,分析资料中采集的尿液标本进行细菌培养、分离、鉴定及其药敏试验结果,以及致病菌对不同氟喹诺酮类药物的耐药率。结果:156例泌尿系统感染患者的尿液标本中,分离出174株致病菌株,其主要以大肠埃希菌、肠球菌、表皮葡萄球菌为主;大肠埃希菌产超广谱β-内酰胺酶(ESBLs)对左氧氟沙星、氧氟沙星、诺氟沙星、环丙沙星的耐药率高于非ESBLs,对肠球菌高水平庆大霉素耐药率(HLGR)高于非HLGR(P<0.05);而表皮葡萄球菌MRSE对氧氟沙星、环丙沙星的耐药率高于非MRSE(P<0.05);采用不同氟喹诺酮类药物治疗后细菌的消除率为91.67%。结论:泌尿道感染患者病原菌以大肠埃希菌为主,大肠埃希菌应明确ESBLs、MRSE、HLGR菌株,根据其多重耐药情况合理使用不同氟喹诺酮类药物治疗,有效清除致病菌。     

Human Multidrug Resistance Associated Protein 4 Confers Resistance to Camptothecins

Purpose The multidrug resistance associated protein (MRP) 4 is a member of the adenosine triphosphate (ATP)-binding cassette transporter family. Camptothecins (CPTs) have shown substantial anticancer activity against a broad spectrum of tumors by inhibiting DNA topoisomerase I, but tumor resistance is one of the major reasons for therapeutic failure. P-glycoprotein, breast cancer resistance protein, MRP1, and MRP2 have been implicated in resistance to various CPTs including CPT-11 (irinotecan), SN-38 (the active metabolite of CPT-11), and topotecan. In this study, we explored the resistance profiles and intracellular accumulation of a panel of CPTs including CPT, CPT-11, SN-38, rubitecan, and 10-hydroxy-CPT (10-OH-CPT) in HepG2 cells with stably overexpressed human MRP4. Other anticancer agents such as paclitaxel, cyclophosphamide, and carboplatin were also included. Methods HepG2 cells were transfected with an empty vehicle plasmid (V/HepG2) or human MRP4 (MRP4/HepG2). The resistance profiles of test drugs in exponentially growing V/HepG2 and MRP4/HepG2 cells were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay with 4 or 48 h exposure time of the test drug in the absence or presence of various MRP4 inhibitors. The accumulation of CPT-11, SN-38, and paclitaxel by V/HepG2 and MRP4/HepG2 cells was determined by validated high-performance liquid chromatography methods. Results Based on the resistance folds from the MTT assay with 48 h exposure time of the test drug, MRP4 conferred resistance to CPTs tested in the order 10-OH-CPT (14.21) > SN-38 carboxylate (9.70) > rubitecan (9.06) > SN-38 lactone (8.91) > CPT lactone (7.33) > CPT-11 lactone (5.64) > CPT carboxylate (4.30) > CPT-11 carboxylate (2.68). Overall, overexpression of MRP4 increased the IC₅₀ values 1.78- to 14.21-fold for various CPTs in lactone or carboxylate form. The resistance of MRP4 to various CPTs tested was significantly reversed in the presence of dl-buthionine-(S,R)-sulfoximine (BSO, a γ-glutamylcysteine synthetase inhibitor), MK571, celecoxib, or diclofenac (all MRP4 inhibitors). In addition, the accumulation of CPT-11 and SN-38 over 120 min in MRP4/HepG2 cells was significantly reduced compared to V/HepG2 cells, whereas the addition of celecoxib, MK571, or BSO significantly increased their accumulation in MRP4/HepG2 cells. There was no significant difference in the intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells, indicating that P-glycoprotein was not involved in the observed resistance to CPTs in this study. MRP4 also conferred resistance to cyclophosphamide and this was partially reversed by BSO. However, MRP4 did not increase resistance to paclitaxel, carboplatin, etoposide (VP-16), 5-fluorouracil, and cyclosporine. Conclusions Human MRP4 rendered significant resistance to cyclophosphamide, CPT, CPT-11, SN-38, rubitecan, and 10-OH-CPT. CPT-11 and SN-38 are substrates for MRP4. Further studies are needed to explore the role of MRP4 in resistance, toxicity, and pharmacokinetics of CPTs and cyclophosphamide.     

Aminoglycoside Adaptive Resistance

Aminoglycoside adaptive resistance is defined as reduced antimicrobial killing in originally susceptible bacterial populations after initial incubation with aminoglycoside. It is observed in vitro and in vivo, most commonly with Pseudomonas aeruginosa. It appears to correlate with a marked reduction in intracellular aminoglycoside accumulation, although its specific mechanism and the cellular structures responsible remain unknown in P. aeruginosa. Recent work suggests that adaptive resistance develops coincident with cytoplasmic membranes protein changes and regulated expression of genes in the anaerobic respiratory pathway of the organism. It is clinically most relevant in immunocompromised patients and in those with serious infections, especially infections due to gram-negative rods. Treatment of these patients by targeting high peak concentration:minimum inhibitory concentration ratios with once-daily dosing may result in the best outcome. A major unresolved issue concerns the effect of combination therapy on the development of aminoglycoside adaptive resistance.     

抗HIV药物的耐药问题

原发耐药　一例有争议的病例报道引发争论　有关抗HIV药物原发耐药的研究由于纽约市的一例具有争议性的病例报道而蒙上了阴影,该报道中的男性患者感染了HIV-3型耐药病毒,大概在3～20个月之内就迅速发展到严重免疫抑制（CD4＋细胞数量小于50细胞/mcL）.争议主要集中在以下方面：对于人类而言,如此之快的病情进展是否极为罕见;具有这种罕见却令人震惊特征（即HIV-3型耐药和极快的病程进展）的单一病例是否值得投入这么多的精力去关注.在第12届逆转录病毒和机会性感染大会上召开的特别会议使得对该病例的科学评价和讨论得以进行.Markowitz等人刚刚发表了一篇有关这一病例详细描述的文章.有理由相信,这场争论不应针对该病例是否值得引起广泛关注,而应该去发掘以往抗HIV药物原发耐药报道中的疏忽之处.     

Resistance to quinolones

Resistance to quinolones is only due to mutations. The mechanism and the range of quinolones involved, depend on the locus of the chromosomal mutation e.g. a mutation in the gyr A locus is associated with resistance due to changes in the gyrase. Using high inoculain vitro, varying, but relatively low mutation rates of resistance to fluoroquinolones have been found (10⁻⁶-10⁻¹²).In vitro transfers of bacterial strains in increasing concentrations of quinolones yield parallel increases of the MIC's of most quinolones; however, the MIC's of the most active quinolones like ciprofloxacin usually remain below concentrations achievablein vivo. Exceptions are MIC's forPseudomonas aeruginosa and staphylococci. Combined resistance to quinolones and other antibiotics was observed afterin vitro transfers as well as in mutants (10⁻⁶-10⁻⁸) isolated from a high inoculum. Changes in the outer membrane proteins have been found in these mutants. Clinical resistance to fluoroquinolones is rare except inPseudomonas aeruginosa and staphylococci.

     

药物基因组学与抗血小板药物抵抗研究进展

阿司匹林和氯吡格雷是急性冠状动脉综合征和经皮冠状动脉介入术后的基础抗栓药物,但其疗效存在明显个体差异,部分患者出现药物抵抗。本文综述基因多态性与上述药物反应变异性的关联,以促进基因检测有助于治疗方案的决策。     

胰岛素抵抗和氯吡格雷抵抗的关系研究

目的探讨心绞痛合并糖尿病患者胰岛素抵抗和氯吡格雷抵抗的相互关系。方法选取河北省邯郸市第二医院符合条件患者共计85例,给予氯吡格雷维持量75mg/d,将其分为氯吡格雷抵抗组与对照组,测定两组患者二磷酸腺苷诱导的血小板聚集率(ADP)、胰岛素敏感指数(ISI)和空腹血糖(FBG)、空腹胰岛素(FINS)等值,对所得结果进行统计学分析。结果所有患者中有氯吡格雷抵抗13例(氯吡格雷抵抗组),其与对照组的各指标比较结果发现,各指标均有统计学意义(P<0.05)。结论冠心病合并糖尿病患者的氯吡格雷抵抗发生率约为15.3%,胰岛素抵抗和氯吡格雷抵抗发生率之间有明确相关性。     

Resistance to anti-VEGF agents

The number of anti-angiogenic agents developed for clinical use has risen greatly over the past decade. Currently, more than 80 are in trials ranging from phase I through to phase III studies and many more are in preclinical evaluation. Much hope was envisaged for these new agents to become the panacea of anti-tumoural treatment. Unfortunately the single agent activity to date has proven to be disappointing although one trial has recently reported a survival advantage when chemotherapy was administered with anti-VEGF antibodies in the setting of advanced colorectal cancer. To an extent, this may be due to great expectations of cytostatic compounds, but recently many factors have been examined to explain the differences between clinical and experimental findings. In this review, some of the factors responsible for the discrepancy are examined, with a specific focus on inhibitors of VEGF. The key factors responsible for the lack of activity are tumour heterogeneity and redundancy in the VEGF signalling system. An increased understanding of these factors is critical to the development of effective anti-angiogenic agents and need to be taken into account as new generations of drugs emerge.     

鲍曼不动杆菌耐药性演变及抗菌药物使用相关性研究

目的 分析鲍曼不动杆菌耐药性与相关抗菌药物用药频度的相关性及鲍曼不动杆菌对不同抗菌药物耐药率的相关性,旨在为抗菌药物临床合理使用及医院感染防控提供科学依据。方法 采用纸片琼脂扩散法测定相关抗菌药物对鲍曼不动杆菌的敏感率,根据世卫组织推荐的限定日剂量（defined daily dose,DDD）值原理及方法,确定DDD值并计算抗菌药物用药强度（antibiotics use density,AUD）,并用SPSS 17.0进行数据分析。结果 2013-2017年汕头大学医学院第一附属医院鲍曼不动杆菌检出率逐年降低,相关抗菌药物总的AUD值从2014年起逐年下降,鲍曼不动杆菌对环丙沙星、头孢曲松、头孢吡肟的耐药率均在2014年后进入下降趋势,对亚胺培南的耐药率在2015年后进入下降趋势。各相关抗菌药物的AUD与鲍曼不动杆菌耐药率的相关性不具有显著性差异,鲍曼不动杆菌对各相关抗菌药物的耐药率间,除替加环素外,大部分都具有相关性,且具有显著性差异（P<0.05）。结论 加强医院感染管理、合理使用抗菌药物是治疗鲍曼不动杆菌感染和降低耐药率的关键,同时还要了解鲍曼不动杆菌耐药率高发的规律,以便更好地控制感染,减少耐药发生。