Targeting of Antibiotics in Bacterial Infections Using Pegylated Long-Circulating Liposomes

Abstract

PEGylated long-circulating liposomes were used as a delivery system of antibiotics providing enhancements in antibiotic pharmacokinetics and penetration to infected sites. Pharmacokinetic and therapeutic efficacy studies were performed in the model of unilateral pneumonia/septicemia caused by Klebsiella pneumoniae in rats with intact host defense or leukopenic rats. Gentamicin was encapsulated in PEGylated liposomes designed to achieve delivery of antibiotic to the infected left lung tissue. Our data show that the efficacy of liposomal gentamicin was superior to free gentamicin particularly in difficult to treat infection due to impaired host defense (leukopenia) or low antibiotic susceptibility of the infectious organism. In leukopenic rats infected with a high gentamicin-susceptible bacterial strain, free gentamicin must be administered at the maximum tolerated dose to be therapeutically effective. The addition of a single dose of liposome-encapsulated gentamicin on the first day of treatment with free gentamicin leads to full therapeutic efficacy while keeping the antibiotic doses low. In even more difficult to treat infection due to both an impaired host defense (leukopenia) and low gentamicin-susceptibility of the bacterial strain, free gentamicin is not effective, and the addition of the liposome-encapsulated form of gentamicin is needed to achieve full therapeutic efficacy. In this respect, the lipid composition of the liposomes is an important determinant in establishing both sufficient antibiotic levels in blood and sufficient release of antibiotic from the liposomes at the infectious focus.

Ciprofloxacin was encapsulated in PEGylated liposomes designed to serve as a microreservoir of antibiotic during circulation in blood. Our data show that the administration of ciprofloxacin in the liposomal form resulted in slow release of ciprofloxacin from the liposomes over time in blood. Delayed ciprofloxacin clearance, as well as increased and prolonged ciprofloxacin concentrations in blood and tissues was observed. The therapeutic efficacy of liposomal ciprofloxacin was superior to that of free ciprofloxacin. PEGylated liposomal ciprofloxacin was well tolerated in relatively high doses (increasing the maximum tolerated dose for free ciprofloxacin), permitting the administration on a once-a-day schedule without loss in therapeutic efficacy.     

高原地区非淋菌性泌尿生殖道炎支原体感染及药敏分析

了解昆明地区支原体引起非淋菌性泌尿生殖道炎的感染状况以及为其治疗提供敏感的抗生素,采用法国生物梅里埃公司的ＭｙｃｏｐｌａｓｍａＩＳＴ试剂盒对７３例非淋菌性泌尿生殖道炎患者分泌物进行支原体培养鉴定及体外药敏试验,结果检出２０株解脲支原体和６株人型支原体;８例为两种支原体混合感染。     

108例鼠伤寒沙门氏菌医院内感染临床分析

1988年8月至1991年6月在我院婴儿室及儿科病房发生和收治鼠伤寒沙门氏菌病153例,其中108例占64.1％为医院内感染。发病率龄以12个月以内婴幼儿为主占85.6％。连续两年于8月份在婴儿室呈爆发流行共48例占44.4％。本病全年均可发病,以8～10月为发病高峰。医院内感染的主要传染源为院外感染的散发病例收住院的患者及陪住家属的带菌者。消毒隔离制度不严格是引起传播的重要因素。该病原菌耐药性强,尤其院内感染菌株。院内感染延长住院时间,增加病人痛苦及经济负担,因此医院内感染必须引起重视,急待控制。     

微生态制剂对肝硬化患者术后肠道真菌感染的预防作用

目的 :探讨微生态制剂对肝硬化患者术后肠道真菌感染的预防作用。方法 :采用前瞻性研究方法。自 1997年 1月～ 2 0 0 1年 1月先后收治 2 2 0例肝硬化门脉高压症患者 ,行脾切除或脾切除加断流术后分层随机分为两组 ,治疗组 (n=116 )服用微生态制剂 ,对照组 (n=10 4)服用安慰剂 ,分别观察其肠道真菌感染情况。结果 :治疗组和对照组真菌感染率分别是 2 .6 %和 8.7% (P<0 .0 5 ) ,血内毒素 (86 .8± 2 6 .3) pg/ml和 (10 1.5± 6 2 .4) pg/ ml(P<0 .0 5 ) ,血氨 (6 2 .6± 2 8.3)μmol/ L和 (83.0± 2 4.8)μm ol/ L (P<0 .0 5 )。结论 :对门脉高压症患者围手术期使用微生态制剂 ,能防止二重感染和内毒素血症的发生 ,有利于患者术后的康复。     

人巨细胞病毒先天性中枢神经系统感染小鼠模型的建立

将人巨细胞病毒（ＨＣＭＶ）接种至８￣１２周龄Ｂａｌｂ／ｃ雌雄小鼠腹腔后,交配。等雌鼠临产时剖腹取出胎鼠脑双侧大脑皮层,进行病毒分析、病理学检测及用地高辛标记的ＨＣＭＶ寡核苷酸探针对大脑皮层细胞压印片进行原位分子杂交检测。病理学研究结果证实,鼠脑为侵袭性脑膜脑炎性病理改变,并在神经细胞内发现病毒特性性的大的核内嗜碱性包涵体;原位杂交结果显示,病毒核酸存在于受染神经细胞及神经胶质细胞核内及胞浆内;在鼠     

ICU机械通气并发下呼吸道医院感染病原菌的调查分析

目的：分析ICU机械通气并发下呼吸道医院感染病原学构成及耐药情况。为临床防治提供依据。方法：对我院1996年6月-1999年6月3间ICU收住的98例机械通气合并下呼吸道医院感染患者的致病菌及药敏结果进行回顾性调查。结果：共检出致病毒128株,其中革兰阴性细菌（G^-菌）占66.4%（85株）,革兰阳性细菌（G^ 菌）占25.8%(33株）,真菌占7.8%(10株）;前四位致病菌分别为铜绿假单胞菌（24株）,革兰阳性细菌（G^ 菌）占25.8%(33株）,真菌占7.8%(10株）;前四位致病菌分别为铜绿假单胞菌（24株）,金黄色葡萄球菌（22株）,不动杆菌属（21株）,肠杆菌属（18株）,药敏结果显示这类菌株多重耐药现象严重。结论：ICU机械通气并发下呼吸道医院感染病原体构成以G^-菌为主,其药敏试验呈多重耐药,临床应重视病原学检查,开展细菌耐药性监测,合理使用抗菌药物。     

艾滋病合并隐球菌感染17例尸检材料的临床病理学研究

在１５１例艾滋病尸检材料中发现１７例合并隐球菌感染,均经病理学确诊,患者男１５名,女２名,平均４３．６岁。１２例发生脑膜炎、肺炎和淋巴结炎各７例,尚见脾（６例）、肾（５例）等器官受累。９例为播散性感染。病变为慢性肉牙肿性,其中见有隐球菌。本文描述隐球菌性脑膜炎、肺炎等临床病理学表现,并讨论其病变特征与病理诊断问题。     

中药91—4对抗生素相关性腹泻小鼠肠道膜菌群影响的电镜研究

实验用菌群检查和光、电镜相结合的方法,观察了中药９１—４对抗生素相关性腹泻（ＡＡＤ）小鼠肠道膜菌为及其病理学变化的影响。由林可霉素灌胃致小鼠腹泻模型并证实菌群紊乱后,给各治疗组分别灌喂中药,并设自然恢复组,一个疗程后,时各组小鼠进行肠道膜菌群检测分析,同时取回盲部组织标本,分别用光镜及电镜观察肠粘膜结构。结果表明,ＡＡＤ模型组大多数小鼠肠粘膜出现不同程度的损害,治疗一个疗程后,病理组织学及超微结构改变基本恢复正常。９１－４不仅对肠道膜菌群有调整作用,对肠粘膜也有一定的修复作用。     

泌尿生殖道支原体感染及其药物抗性频度研究

目的了解本地区支原体引起泌尿生道感染的状况及其药物抗性频度,为临床治疗支原体感染提供参考依据.方法取男性尿道分泌物或前列腺液和女性宫颈分泌物,应用Mycoplasma IST综合试剂盒进行支原体定量培养鉴定和药物抗性频度试验,同时检测沙眼衣原体(CT)、白色念珠菌和淋球菌(NG).结果2 023例泌尿生殖道感染患者中,747例支原体培养阳性,阳性率36.93%; 其中女性为40.16%,男性为23.04%,两者差异有非常显著性(P＜0.01);解脲支原体 (UU)感染(410例,20.27%)显著高于人型支原体(MH)感染(29例,1.43%)和UU+MH混合感染( 308例,15.22%)(P＜0.01).各年龄组支原体感染率,以18～37岁年龄段最高,年龄组间差异有非常显著性 (P＜0.01).747例支原体感染患者中,合并CT感染59例,占7 .90%,合并白色念珠菌感染 81例,占10.84%;合并NG感染39例,占5.22%.药物抗性频度研究结果显示对红霉素的抗药频率最高,占65.21%,对氧氟沙星和四环素的抗药频率次之,分别为28.53%和11.09%,对强力霉素、原始霉素和交沙霉素的抗药频较低,分别为 4.74%、4.17%和1.52%.比较MH 和UU对6种抗生素的药物抗性频度,MH均显著高于UU(P ＜0.01).结论支原体是引起泌尿生殖道感染的主要病原体之一,交沙霉素和强力霉素应作为本地区目前临床治疗泌尿生殖道支原体感染的首选抗生素.在诊断疾病时,要注意混合感染的可能性.     

水华蓝藻噬藻体对不同条件培养的宿主细胞感染性分析

在从武汉东湖水样中培养分离水华蓝藻噬藻体(Planktothrix agardhii Virus from Lake Donghu,PaV-LD)的基础上,对在不同条件培养的宿主蓝藻细胞中,PaV-LD增殖效率及裂解作用进行了测定分析。分别将PaV-LD接种到生长期、半连续培养更新率或光照不同的宿主蓝藻液中,并采用稀释培养计数(Mostprobable number,MPN)方法与电镜观察,测定子代PaV-LD释放量及宿主细胞的裂解作用。结果显示:对数生长期宿主蓝藻单个细胞中子代PaV-LD的平均释放量为350感染单位(Infectious Units,IU/cell),显著高于稳定生长期的平均释放量110 IU/cell。在用新鲜培养基更新率为0%、35%、50%和65%的半连续培养宿主蓝藻中,接种PaV-LD 5d之后,噬藻体的释放量分别约为50 IU/cell、70 IU/cell、220 IU/cell或310 IU/cell,表明子代PaV-LD释放率随培养基更新率的增加而显著提高。在光照条件下感染3—4d后,宿主蓝藻细胞充分裂解,并释放大量子代PaV-LD,滴度可由初始7.00×103IU/mL快速增加到8.56×107IU/mL;但在遮光条件下,同样感染的蓝藻细胞未见裂解,也检测不到释放的子代噬藻体。电镜观察显示,在光照条件下感染的蓝藻细胞类囊体膜结构消失,而大量子代PaV-LD颗粒主要分布在原有类囊体的部位。显然,宿主蓝藻细胞的培养条件和状态可能对获得噬藻体纯培养有决定性影响。     

一种新的视觉皮层简单细胞工作机制的模型

提出了一种基于独立元分析（ICA）的视觉皮层简单细胞工作机制的模型。用Gabor函数逼近对自然图像进行ICA而获得的基函数,揭示了ICA基函数与视觉皮层简单细胞感受野反应间存在内在的关系。并对水平条纹的图像进行ICA,模拟在特殊视觉环境下生长的幼年动物的视觉皮层发育过程,证实了1970年Blakemore和Cooper在幼猫上的实验结果。从而说明ICA可以模拟动物的视觉皮层简单细胞工作过程。     

动物单种群动态的ALLEE效应的数学模型及其解的性态

本文根据单种群动态ALLEE效应的特点,引入一个适当的数学模型,并对其解的振动性、有界性和渐近稳定性进行了研究。     

THE DISTINCTIVE FOOTPRINTS OF LOCAL HITCHHIKING IN A VARIED ENVIRONMENT AND GLOBAL HITCHHIKING IN A SUBDIVIDED POPULATION

Loci with higher levels of population differentiation than the neutral expectation are traditionally interpreted as evidence of ongoing selection that varies in space. This article emphasizes an alternative explanation that has been largely overlooked to date: in species subdivided into large subpopulations, enhanced differentiation can also be the signature left by the fixation of an unconditionally favorable mutation on its chromosomal neighborhood. This is because the hitchhiking effect is expected to diminish as the favorable mutation spreads from the deme in which it originated to other demes. To discriminate among the two alternative scenarios one needs to investigate how genetic structure varies along the chromosomal region of the locus. Local hitchhiking is shown to generate a single sharp peak of differentiation centered on the adaptive polymorphism and the standard signature of a selective sweep only in those subpopulations in which the allele is favored. Global hitchhiking produces two domes of differentiation on either side of the fixed advantageous mutation and signatures of a selective sweep in every subpopulation, albeit of different magnitude. Investigating population differentiation around a locus that strongly differentiates two otherwise genetically similar populations of the marine mussel Mytilus edulis, plausible evidence for the global hitchhiking hypothesis has been obtained. Global hitchhiking is a neglected phenomenon that might prove to be important in species with large population sizes such as many marine invertebrates.     

台湾虫草的被毛孢无性型新种及其对黄粉虫的侵染研究

报道采自安徽省黄山风景区的台湾虫草Cordycepsformosana,多批次收集弹射的子囊孢子分离得到其无性型,经鉴定为一被毛孢新种,命名为黄山被毛孢Hirsutellahuangshanensis。黄山被毛孢在米饭培养和自制的虫草培养基上均能长出子实体,其菌落及子实体颜色与天然虫草较为相似,但未见成熟的子囊壳。应用黄山被毛孢RCEF0868菌株对饲喂昆虫黄粉虫进行感染试验,结果表明:黄粉虫在菌落接触感染、刚蜕皮幼虫的穿刺接种和孢子浓度1.0×107/ml浸蘸处理下,获得了相对较高的侵染率,分别达到30%、25%和25%,刚蜕皮幼虫一般比深色幼虫组其侵染率较高,1×105/ml孢子浓度浸蘸试虫不论是刚蜕皮或老熟幼虫均不能感染。10d后被感染的黄粉虫形成僵虫,继续保湿培养20d后,体表节间膜处形成白色菌膜,粘片镜检表明感染真菌即为供试菌株。40d后,可见子实体原基及孢梗束,尚未见成熟的子囊壳。