CN111939156B - 一种联合抗菌药物组合物及其应用 - Google Patents
一种联合抗菌药物组合物及其应用 Download PDFInfo
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- CN111939156B CN111939156B CN202010868371.7A CN202010868371A CN111939156B CN 111939156 B CN111939156 B CN 111939156B CN 202010868371 A CN202010868371 A CN 202010868371A CN 111939156 B CN111939156 B CN 111939156B
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- berberine
- sulbactam
- meropenem
- acinetobacter baumannii
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Abstract
本发明提供了一种包含小檗碱和抗生素的联合抗菌药物组合物,所述抗生素选自舒巴坦、替加环素、阿米卡星、环丙沙星、美罗培南和四环素中的一种或两种。小檗碱与抗生素的联合用药对抗多重耐药鲍曼不动杆菌效果显著,抑菌指数小于1,二者表现为叠加或协同作用;能够有效的降低抗生素的MIC值;还能够使多重耐药鲍曼不动杆菌对抗生素复敏。本发明的联合抗菌药物组合物对于耐药菌、特别是多重耐药鲍曼不动杆菌具有显著的抑制作用。
Description
技术领域
本发明涉及药物组合物领域,具体涉及一种包含小檗碱和抗生素的联合抗菌药物组合物及其应用。
背景技术
鲍曼不动杆菌是一类革兰氏阴性杆菌,是非运动型、过氧化氢酶阳性、氧化酶阴性和严格需氧的细菌,它被认为是造成医院感染的重要病原菌之一。鲍曼不动杆菌可以引发多种获得性疾病,包括肺炎、皮肤和软组织感染、伤口感染、尿路感染等,其中,死亡率最高的感染是需要采用呼吸机辅助治疗的肺炎,在患有基础疾病或接受过重大外科手术的患者中更为常见,约占40%-70%。在过去的十多年中,鲍曼不动杆菌的抗生素耐药性显著提高,中国细菌耐药监测网细菌耐药性监测系统的报告显示,在2005年至2014年之间,碳青霉烯类耐药鲍曼不动杆菌的耐药性从31%增加到66.7%。考虑到鲍曼不动杆菌(Multidrug-resistant Acinetobacter baumannii,MDRAb)多重耐药性日益增强的困境以及新型抗生素开发的相对困难等因素,联合用药已经成为一种可以改善治疗效果并可能预防出现新的耐药性的潜在选择。目前临床联合治疗方案主要集中为抗生素与抗生素两两组合,基于感染细菌的耐药谱,可以选择合适的联合用药组合。
小檗碱,又称黄连素,是一种淡黄色的异喹啉生物碱,其广泛存在于小檗属植物的根、根状茎和茎皮中。盐酸小檗碱是小檗碱最常见的一种形式,被认为是一种具有多种医学潜力的药物,具有抗菌、抗病毒、止泻、退热和抗炎等作用。在中国,含有小檗碱的中药如黄连被用作治疗胃肠炎、腹痛和腹泻的传统抗菌药物,其使用时间已经超过2000年,积累了大量的临床研究数据,表明小檗碱是一种安全的临床抗菌剂。
随着鲍曼不动杆菌耐药性日益剧增,其对传统意义上的治疗抗生素如碳青霉烯类药物产生耐药性,单独用药难以奏效。一些新型抗生素例如替加环素或粘菌素,虽然耐药率相对较低,但治疗成本较高且存在一定副作用。目前临床上多采用联合用药对抗多重耐药鲍曼不动杆菌造成的感染,但有时部分菌株耐药谱相对较广,可供选择的抗生素组合受限。国内虽然有美罗培南和舒巴坦或者法罗培南和他唑巴坦联合用药对抗多重耐药鲍曼不动杆菌的相关专利报道,但二者联用复敏效果不理想,抗生素浓度仍旧处于细菌耐药范围之内。
因此,寻找一种合理的抗菌药物组合具有重要的临床意义。
发明内容
为改善上述技术问题,本发明提供了一种联合抗菌药物组合物,其包含小檗碱与抗生素的组合;
其中,所述抗生素选自舒巴坦、替加环素、阿米卡星、环丙沙星、美罗培南和四环素中的一种或两种。
根据本发明的实施方案,所述小檗碱可以为其盐的形式,例如盐酸小檗碱或硫酸小檗碱。
根据本发明的实施方案,所述小檗碱和抗生素的重量比可以为(1-4096):1,例如(1-1024):1,如(2-512:1),示例性为4:1、8:1、16:1、32:1、64:1、128:1、256:1、512:1或4096:1。
根据本发明的实施方案,所述联合抗菌药物组合物包含以下的组合之一:
(1)盐酸小檗碱与舒巴坦的组合,二者的重量比可以为(2-512):1,例如(4-256):1,(8-128):1,示例性地为2:1、4:1、8:1、16:1、32:1、64:1或128:1;
(2)盐酸小檗碱与替加环素的组合,二者的重量比可以为(1-4096):1,例如(1-256):1、(2-128):1,(4-64):1,示例性地为8:1、16:1、32:1、64:1或4096:1;
(3)盐酸小檗碱与环丙沙星的组合,二者的重量比可以为(1-1024):1,例如为(2-512:1),示例性为4:1、8:1、16:1、32:1、64:1、128:1、256:1或512:1;
(4)盐酸小檗碱与美罗培南的组合,二者的重量比可以为(2-512):1,例如(4-256):1,(8-128):1,示例性地为8:1、16:1、32:1、64:1或128:1;
(5)盐酸小檗碱与阿米卡星的组合,二者的重量比可以为(1-256):1,例如为(2-128:1),示例性为4:1、8:1、16:1、32:1、64:1、128:1或256:1;
(6)盐酸小檗碱与四环素的组合,二者的重量比可以为(1-256):1,例如为(2-128:1),示例性为4:1、8:1、16:1、32:1、64:1、128:1或256:1。
优选地,所述联合抗菌药物组合物包含上述(1)-(4)的组合之一。
根据本发明的实施方案,所述小檗碱在组合物中的重量百分含量可以为5.0%-90.0%,例如为10.0%-85.0%,15.0%-80.0%,20%-75.0%,25%-70%;所述抗生素在组合物中的重量百分含量可以为0.01%-50.0%,例如为0.05%-45.0%,0.1%-40.0%,0.2%-35%,0.3%-30%。
根据本发明的实施方案,所述联合抗菌药物组合物还可包含药学上可接受的载体、赋形剂或溶剂。
根据本发明的实施方案,所述联合抗菌药物组合物可通过常规方法制成口服制剂或注射剂,例如片剂、颗粒剂、胶囊剂、缓释制剂、注射液、粉针剂或输液剂等。
所述药学上可接受的载体或赋形剂包括但不限于填充剂、崩解剂、粘合剂、润湿剂、润滑剂、矫味剂、pH调节剂、等渗调节剂、抗氧化剂、金属离子螯合剂等。
可用于本发明的填充剂的实例包括但不限于微晶纤维素、乳糖、甘露醇、淀粉或糊精,或其中两种或更多种的组合。
可用于本发明的崩解剂的实例包括但不限于羧甲基淀粉钠、交联羧甲基纤维素钠、羧甲基淀粉钠、羟丙基淀粉、交联聚维酮、低取代羟丙基纤维素或玉米淀粉,或其中两种或更多种的组合。
可用于本发明的粘合剂的实例包括但不限于羟丙甲纤维素、聚维酮、甲基纤维素或羧甲基纤维素钠,或其中两种或更多种的组合。
可用于本发明的润湿剂的实例包括但不限于水或乙醇水溶液。
可用于本发明的润滑剂的实例包括但不限于硬脂酸镁、滑石粉或微粉硅胶,或其中两种或更多种的组合。
可用于本发明的矫味剂的实例包括但不限于蔗糖、甜菊苷或阿司巴甜,或其中两种或更多种的组合。
可用于本发明的pH调节剂的实例包括但不限于氢氧化钠、盐酸、磷酸、磷酸盐、柠檬酸、柠檬酸盐、枸橼酸、枸橼酸盐、醋酸、醋酸盐、甘氨酸或赖氨酸,或其中两种或更多种的组合;根据本发明的实施方案,pH调节剂调节pH值在5.5~8.5之间,优选为6.5~7.5。
可用于本发明的等渗调节剂的实例包括但不限于氯化钠、葡萄糖、甘油、山梨醇、麦芽糖、甘露糖醇或丙二醇,或其中两种或更多种的组合。
可用于本发明的抗氧剂的实例包括但不限于亚硫酸钠、亚硫酸氢钠或焦亚硫酸钠,或其中两种或更多种的组合。
可用于本发明的金属螯合剂的实例包括但不限于乙二胺四乙酸(EDTA)或乙二胺四乙酸钠盐(EDTA-Na),特别是乙二胺四乙酸二钠盐。
可用于本发明的药物上可接受的溶剂为注射用水。
本发明还提供所述联合抗菌药物组合物用于制备抗菌药物的应用。优选地,所述抗菌药物用于对抗鲍曼不动杆菌尤其是多重耐药鲍曼不动杆菌引起的感染。
有益效果
1.本发明选用的中药单体成分盐酸小檗碱价格低廉,易于获得,且已经积累了2000多年的临床经验,基本无毒副作用。
2.盐酸小檗碱与抗生素联用时工作浓度位于16-512mg/L之间。针对不同菌株而言,工作浓度依据盐酸小檗碱的MIC确定。对于菌株MDRAb-1(盐酸小檗碱MIC为256mg/L)而言,工作浓度位于16-128mg/L之间,浓度为128mg/L时效果显著;对于菌株MDRAb-2(盐酸小檗碱MIC为1024mg/L)而言,工作浓度位于128-512mg/L之间,浓度为256、512mg/L时效果显著。
3.小檗碱与抗生素联合用药对抗多重耐药鲍曼不动杆菌效果显著,抑菌指数小于1,表现为叠加或协同作用;使抗生素的MIC值降低至少2倍;还能够使多重耐药鲍曼不动杆菌对抗生素复敏。因此,本发明的联合抗菌药物组合物对于耐药菌、特别是多重耐药鲍曼不动杆菌具有显著的抑制作用。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例
利用96孔板微量肉汤稀释法测定选用抗生素(舒巴坦、替加环素、阿米卡星、环丙沙星、美罗培南、四环素)与盐酸小檗碱对抗多重耐药鲍曼不动杆菌的最小抑菌浓度MIC值;在测定MIC值的基础上,利用棋盘法设计,测定盐酸小檗碱与舒巴坦、替加环素、环丙沙星、美罗培南的部分抑菌指数FIC值,进而判定二者联用的协同抑菌效果以及盐酸小檗碱协助抗生素对抗多重耐药鲍曼不动杆菌恢复敏感的作用,即复敏。
步骤说明:
1.菌株选择:实验选取了两株多重耐药鲍曼不动杆菌(MDRAb-1和MDRAb-2),其对传统喹诺酮类、先锋霉素类、氨基糖苷类、碳青霉烯类、青霉素类、四环素类等抗生素耐药。
2.抗菌药物的配制:
所有抗菌药物均使用无菌无盐离子蒸馏水配制得到。盐酸小檗碱、舒巴坦、美罗培南配制母液浓度为2048mg/L,替加环素母液浓度为2560mg/L,阿米卡星、四环素母液浓度为4096mg/L,环丙沙星母液浓度为64mg/L。
3.测定最小抑菌浓度MIC
按照美国临床实验室标准化协会CLSI文件M100的实验指导方案,使用微量肉汤稀释法测定抗菌药物的MIC,所有测试均在阳离子调节的Mueller Hinton肉汤(CAMHB)中进行。在96孔板中每孔中加入100μL一系列二倍稀释的抗菌药物稀释液,将细菌浓度调至0.5麦氏浊度(约1.5×108CFU/mL),再稀释150倍,然后添加到每个孔中(每孔100μL),使得细菌终浓度约为5×105CFU/mL。带有细菌悬液但未添加抗菌剂的孔用作阳性生长对照,仅添加CAMHB培养基的孔用作阴性对照。将96孔板至于孵育箱中于35℃孵育20-24小时后观察结果,检测结果见表1。
MIC被定义为抑制90%以上细菌生长的最低抗菌剂浓度,同时,此参考下大致等同于无肉眼可见的细菌生长。每个浓度重复3个孔,至少进行3次独立测定。大肠杆菌Escherichia coli ATCC 25922用作质控菌株。
抑制率=(1-(OD600nm药物处理组-OD600nm阴性对照组)/(OD600nm阳性对照组-OD600nm阴性对照组))×100%
目前尚无替加环素和舒巴坦对鲍曼不动杆菌的CLSI敏感性判断点。因此,此研究使用氨苄青霉素/舒巴坦组合的CLSI标准用于判定舒巴坦敏感性判断点(≤4mg/L,敏感;8mg/L,中介;≥16mg/L,抗性);使用美国食品药品监督管理局(FDA)规定的标准判定替加环素敏感性判断点(≤2mg/L,敏感;4-6mg/L,中介;≥8mg/L,抗性)。
表1抗菌剂最小抑菌浓度MIC
注:R,耐药;M,中介;S,敏感。
4.测定药物联合使用的部分抑菌指数FIC值
利用棋盘法设计确定抗生素与盐酸小檗碱对抗多重耐药鲍曼不动杆菌的协同效应。实验流程如下:基于先前确定的MIC值制备一系列两倍稀释的抗菌剂。然后,在水平方向上添加50μL的经一系列二倍稀释的抗生素(舒巴坦、替加环素、环丙沙星、美罗培南),在垂直方向上添加50μL的经一系列二倍稀释的盐酸小檗碱,并将100μL细菌悬浮液添加到96孔板中,使其最终浓度约为5×105CFU/mL。将96孔板置于孵育箱中于35℃孵育20-24小时后观察结果。根据部分抑制指数(FIC)确定组合之间的相互作用。
FIC值计算公式如下:
FIC=(抗生素联合MIC)/(抗生素单独MIC)+(盐酸小檗碱联合MIC)/(盐酸小檗碱单独MIC)
将FIC值定义如下:协同作用,FIC≤0.5;叠加作用,0.5<FIC≤1;无关作用,1<FIC≤2;拮抗作用,FIC>2。
表2盐酸小檗碱与抗生素联用组合的FIC值范围
注:盐酸小檗碱与抗生素配比时浓度分别为16、32、64、128mg/L(MDRAb-1)以及64、128、256、512mg/L(MDRAb-2)
表3盐酸小檗碱与抗生素联用部分抑菌指数FIC值
注:(1)R,耐药;M,中介;S,敏感。
(2)标注a为复敏组合及相关数据。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (14)
1.一种联合抗菌药物组合物,其特征在于,其包含以下的组合之一:
(1)盐酸小檗碱与舒巴坦的组合,二者的重量比为 (32-64):1;
(2)盐酸小檗碱与美罗培南的组合,二者的重量比为 (32-64):1;
所述抗菌药物用于对抗鲍曼不动杆菌引起的感染。
2.根据权利要求1所述的组合物,其特征在于,所述小檗碱在组合物中的重量百分含量为5.0%-90.0%;所述舒巴坦或美罗培南在组合物中的重量百分含量为0.01%-50.0%。
3.根据权利要求1或2所述的组合物,其特征在于,所述小檗碱在组合物中的重量百分含量为10.0%-85.0%。
4.根据权利要求1或2所述的组合物,其特征在于,所述小檗碱在组合物中的重量百分含量为15.0%-80.0%。
5.根据权利要求1或2所述的组合物,其特征在于,所述小檗碱在组合物中的重量百分含量为20%-75.0%。
6.根据权利要求1或2所述的组合物,其特征在于,所述小檗碱在组合物中的重量百分含量为25%-70%。
7.根据权利要求1或2所述的组合物,其特征在于,所述舒巴坦或美罗培南在组合物中的重量百分含量为0.05%-45.0%。
8.根据权利要求1或2所述的组合物,其特征在于,所述舒巴坦或美罗培南在组合物中的重量百分含量为0.1%-40.0%。
9.根据权利要求1或2所述的组合物,其特征在于,所述舒巴坦或美罗培南在组合物中的重量百分含量为0.2%-35%。
10.根据权利要求1或2所述的组合物,其特征在于,所述舒巴坦或美罗培南在组合物中的重量百分含量为0.3%-30%。
11.根据权利要求1或2所述的组合物,其特征在于,所述联合抗菌药物组合物还包含药学上可接受的载体、赋形剂或溶剂。
12.根据权利要求1或2所述的组合物,其特征在于,所述联合抗菌药物组合物通过常规方法制成口服制剂或注射剂。
13.权利要求1-12任一项所述组合物用于制备抗菌药物的应用,所述抗菌药物用于对抗鲍曼不动杆菌引起的感染。
14.根据权利要求13所述的应用,其特征在于,所述抗菌药物用于对抗多重耐药鲍曼不动杆菌引起的感染。
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