CN117940127A - 治疗多种耐药细菌感染的制剂 - Google Patents
治疗多种耐药细菌感染的制剂 Download PDFInfo
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- CN117940127A CN117940127A CN202380013487.4A CN202380013487A CN117940127A CN 117940127 A CN117940127 A CN 117940127A CN 202380013487 A CN202380013487 A CN 202380013487A CN 117940127 A CN117940127 A CN 117940127A
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- avibactam
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- biapenem
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Abstract
本发明涉及医药领域,尤其涉及抗菌治疗,主要用于治疗由产生多种耐药碳青霉烯酶的细菌引起的严重和极其严重的医院感染。本发明建议使用一种由比阿培南和阿维巴坦(avibactam)按4:1至1:2的比例混合而成的制剂,来治疗由产生碳青霉烯酶的肠杆菌科、肉毒杆菌属和假单胞菌属的多种耐药细菌引起的感染性疾病。本发明提供了比阿培南和阿维巴坦(avibactam)对产生碳青霉烯酶的革兰氏阴性菌的协同作用。
Description
本发明涉及医药领域,尤其涉及抗菌治疗,即基于碳青霉烯类的β-内酰胺类抗生素比阿培南与来自二氮双环辛烷类的β-内酰胺酶抑制剂阿维巴坦的组合形成的一种新药物,主要用于治疗由多种耐性细菌(包括产生碳青霉烯霉的细菌)引起的重症和极重症的感染性疾病。
医院(院内)感染是限制现代高科技发展的重要因素之一。医院感染最可能发生在具有大面积创伤、免疫抑制和接受侵入性手术的患者身上。根据世卫组织的一份研究报告显示,在具有混合患者群体的高收入国家,医院感染率是每100个患者有7.6个发作,而在中低收入国家,每100个患者有10.1个发作[1]。同时,在一些发达国家,医院感染的发病率较低,2016年在德国,4.6%的住院患者发生了院内感染[2],2013年在美国,4.0%的住院患者发生了院内感染[3]。在俄罗斯联邦(Russian Federation)中,仅有一项研究对住院感染的发病率进行了前瞻性评估[4],其发病率为7.6%,高于最有利的国家,但总体上与发达国家的指标相符。重症监护病房的院内感染率最高(26.28%)。据统计,俄罗斯每年发生的医院内感染病例为2.3百万例[5]。
医院感染的主要形式包括呼吸道感染、泌尿道感染、手术区域感染以及与与静脉导管相关的血流感染。大部分医院感染是由范围有限的病原体引起的,其中包括肠杆菌科(Enterobacteres)、假单胞菌属(Pseudomonas spp.)、不动杆菌属(Acinetobacter spp.)、金黄色葡萄球菌(Staphylococcus aureus)、凝固酶-阴性葡萄球菌(coagasenegativestaphycocci)、艰难梭菌(C.difficile)和肠球菌属(Enterococcus spp)。病毒和真菌在医院感染病因中的作用较小。所列出的微生物的相对作用因时间、是否存在有效的感染控制系统、患者群体、科室和/或机构的具体情况而异[6]。
医院感染最严重的问题之一是病原体对抗菌素的高度耐药性。抗菌药耐药性的蔓延被国际专业界视为对医疗保健系统的主要全球性威胁。2017年在美国,上述主要的多种耐药病原体造成了超过100,000次的医院感染[7]。
根据2019年最近公布的计算结果,全球级别的感染性病原体抗药性直接导致1.27百万人死亡,并与2019年的4.95百万人死亡有关[8]。
天然抗生素的来源和主要功能并不是完全清楚的;在医学上用于抑制细菌生长的能力可能并不是它们的主要生物学功能。然而,细菌对抗生素的抗药性是与细菌合成这些化合物的能力同时进化而来的[9]。存在这样一种观点:单个物种的抗生素合成能力和抗药性的组合有助于微生物群落的稳定性并防止不良物种的入侵[10]。最可能的是,在现代条件下,医学和农业中使用的抗生素浓度比在自然条件下数十亿年的抗生素浓度高出许多倍时,抗药性的作用正在发生变化,它正在演变为细菌的一种防御机制。
在这种情况下,抗生素在医药和农业中的大规模使用被视为抗药性形成和传播的主要(但不是唯一)驱动力[11-13]。因此,人们认为可以通过减少和优化抗生素的使用来遏制抗药性的传播。一套旨在实现这一目标的措施被称为"抗生素管理"[14,15]。虽然这些措施的实施能在一定程度上减缓抗药性的传播,但要彻底消除已形成的抗药性机制则几乎不可能。为了保持抗感染治疗的高效性,必然需要开发和引进能够克服耐药性的新型抗菌药物。从本质上讲,抗菌化疗的历史就是寻找不断出现的新细菌挑战答案的历史。β-内酰胺类抗生素的例子最能说明这一点。值得注意的是,只有在了解抗生素作用机制和细菌耐药性机制的基础上,才有可能开发出新药。
抗药性形成的遗传机制是通过细菌的附加遗传信息获取,最常见的是移动遗传因子或其自身基因组的突变。从功能角度来看,抗药性机制可分为特异性机制和通用性机制,前者可导致细菌对个体化合物或基团产生抗性(酶失活、靶点修饰),后者可导致细菌对不同基团的药物产生抗药性(主动排泄物、细菌细胞内部运输受损)。
20世纪40年代初,第一种β-内酰胺类抗生素青霉素被引入医疗实践,它的使用为治疗革兰氏阳性菌引起的感染提供了根本性的突破,但这种抗生素的作用并没有扩展到革兰氏阴性菌。1961年,一种半合成的β-内酰胺(氨基青霉素)--氨苄西林被批准用于医疗用途。氨苄西林对一些革兰氏阴性病原体很有效,这是因为氨苄西林增强了通过这些细菌外膜的扩散能力。然而,早在1963年,就出现了第一篇关于分离耐氨苄西林大肠杆菌的报告[16]。耐药性是由于产生了能水解氨苄西林和早期头孢菌素的β-内酰胺酶TEM-1。随后几年,又发现了其他几种具有相同特性的酶(其中最重要的是SHV-1),所有这些酶都被命名为"广谱β-内酰胺酶"(BSBL)。
20世纪70年代和80年代初,第二代和随后几代广谱头孢菌素在β-内酰胺酶的水解作用下产生耐药性,并被引入医疗实践。然而,几乎就在引入这些抗生素之后不久,1985年,首次出现了关于分离抗药性K.ozaenae的报告[17]。研究表明,分离出的菌株能产生一种与SHV-1密切相关的酶,并将其命名为SHV-2。具有降解第二代至第四代头孢菌素的酶被称为"广谱β-内酰胺酶"(ESBs)。许多ESBs是由于TEM-1和SHV-1酶中的氨基酸取代的结果。截至2022年3月,β-内酰胺酶数据库(BLDB):结构和功能中报道了200多种源自TEM-1酶的BSBLs和200多种源自SHV-1酶的BSBLs。20世纪90年代中期,STX-M组的BSBLs异乎寻常地迅速出现和传播。STX-M组β-内酰胺酶的主要宿主是克吕沃尔菌属细菌(Kluyvera)。在这些细菌中,STX-M类β-内酰胺酶的基因位于染色体上;在转移到质粒上后,它们在肠杆菌科的其他代表物种中传播。迄今为止,已描述了250多种这类BSBLs。碳青霉烯类抗生素对BSBL的水解具有耐药性,因此对这些酶的生产者引起的感染仍有临床疗效。β-内酰胺酶抑制剂(如克拉维酸、舒巴坦和他唑巴坦)对BSBL有部分抑制作用,这使得受抑制剂保护的β-内酰胺类药物(哌拉西林/他唑巴坦、头孢哌酮/舒巴坦、头孢吡肟/舒巴坦)在非严重感染中具有临床疗效。
自20世纪80年代末以来,随着BSBL在革兰氏阴性细菌中扩散之后,III-IV代头孢菌素的临床价值逐渐降低。这主要影响到重症监护室。在俄罗斯联邦,如果在1996年检测到第一批分离菌,那么BSBL的检测就会延迟[18]。在1998年,在一些莫斯科医院中,重症监护室中循环的克雷伯菌属中,BSBL产生者的频率超过80%[19]。在随后的几年中,BSBL产生者的活动范围超出了重症监护室,开始在普通病房和院外环境中传播。根据2015-2019年期间的全球多中心研究SMART(抗菌药物耐药性趋势监测研究),大肠杆菌和肺炎克雷伯菌中BSBL产生者的传播频率在不同国家的波动范围非常大(从6%到60%),在俄罗斯,这两个数字分别达到59.1%和28.1%[20]。
由于BSBL的传播,到2000年代中期,第III-IV代头孢菌素在治疗革兰氏阴性菌引起的严重感染中几乎失去了重要性,取而代之的是碳青霉烯类。亚胺培南、美罗培南、厄他培南和多尼培南已经在俄罗斯联邦进行了注册,比阿培南于2021年注册。帕尼培南、舒洛培南(sulopenem)、利替培南和替比培南在其它国家注册,其中后两种用于口服。贝那培南(Benapenem)正在进行临床试验。碳青霉烯类药物的大量使用不可避免地导致了耐药性的产生和蔓延。对碳青霉烯产生抗药性的机制可分为两大类:与碳青霉烯酶的产生有关和无关。在革兰氏阴性菌中,由于各种染色体机制而对碳青霉烯类产生耐药性的个别病例在这些抗生素投入使用后不久就开始发现,但这种耐药性并不普遍。
碳青霉烯类降解酶(碳青霉烯酶)出现后,情况发生了巨大变化,其基因被定位在质粒上。1991年,日本分离出铜绿假单胞菌中的第一个质粒碳青霉烯酶[21]。目前,已知的碳青霉烯酶已超过1000种(β-内酰胺酶数据库(BLDB):结构和功能)。根据活性中心结构的不同,将β-内酰胺酶(包括碳青霉烯酶)分为两类:丝氨酸β-内酰胺酶和金属-β-内酰胺酶。前者的活性中心含有一个丝氨酸氨基酸,而后者则含有一个锌原子。这两类碳青霉烯酶的水解活性机理不同,而且从临床角度来看,最重要的是它们对抑制剂的敏感性不同。
在各种碳青霉烯酶中,有三类最为重要和广泛。其中两类属于丝氨酸β-内酰胺酶:KRS-型(超过100个变体)和OXA-48型(约60个变体),另一类属于金属-β-内酰胺酶NDM型(超过40个变体)。IMI、VIM、SME、IMI、NMC和其它组别的碳青霉烯酶则不太重要。几乎在所有革兰氏阴性菌中都发现了不同组别的碳青霉烯酶,但最重要的是它们在医院细胞病原体中的分布:克雷伯菌属、不动杆菌属和铜绿假单胞菌。碳青霉烯酶在全世界不同地区的分布频率和特殊性显著不同。在俄罗斯联邦,NDM-和OXA-48-类型占优势。在欧洲是-KRAS和OXA-48,在中国是-NDM-和KRAS,在北美是-KRAS[22]。在欧洲,碳青霉烯酶扩散情况最差的是希腊和意大利。在其他地区,中国和印度受到的影响最大。俄罗斯也是碳青霉烯酶传播率极高的国家之一。
碳青霉烯酶的传播已经对全球健康系统造成了严重的打击,因为由耐碳青霉类细菌引起的感染中死亡的风险大约是由易感病原体引起的感染的两倍[23]。因此,为了维持有效的抗生素治疗,如今急需能够克服细菌因产生碳青霉烯酶而对碳青霉烯类抗生素产生抗药性的药物。
克服与碳青霉烯酶的产生相关的抗菌药耐药性的主要方向之一是开发这些酶的特异性抑制剂。保护β-内酰胺抗生素免受β-内酰胺酶作用的策略由来已久,其有效性已得到无数次证实。从20世纪70年代末到80年代中期,开发了β-内酰胺结构β-内酰胺酶的三种不可逆(杀生物)抑制剂并将其投入使用:克拉维酸、舒巴坦和他唑巴坦。在此基础上,又开发了一系列受抑制剂保护的β-内酰胺类药物:阿莫西林/克拉维酸、阿莫西林/舒巴坦、氨苄青霉素/舒巴坦、替卡西林/克拉维酸、哌拉西林/他唑巴坦、头孢哌酮/舒巴坦和头孢吡肟/舒巴坦。这些药物解决了与广谱丝氨酸β-内酰胺酶扩散有关的耐药性问题。然而,事实证明绝大多数BSBL对所列抑制剂的作用不够敏感。在已开发的复方药物中,只有哌拉西林/他唑巴坦和头孢吡肟/舒巴坦对BSBL产生者引起的非严重感染有一定疗效。这些药物对于碳青霉烯酶产生者完全不起作用,对相应的感染无效。
在确定了二氮双环辛烷基团的化合物的抑制活性之后,克服与碳青霉烯酶的产生相关的抗药性问题得到了部分解决。该类化合物对广谱和延伸谱的丝氨酸β-内酰胺酶以及KRAS组的碳青霉烯酶表现出显著的抑制活性,对OXA-48组的碳青霉烯酶具有中等程度的活性,但对金属-β-内酰胺酶没有抑制作用[24]。该类药物的两种代表(阿维巴坦(avibactam)和瑞来巴坦)已获准用于医疗用途的新型抑制剂保护β-内酰胺药物:头孢唑肟/阿维巴坦和亚胺培南/瑞来巴坦。这两种抗生素的临床疗效数据与其体外活性一致,对于由产生KRAS-和OXA-48型碳青霉烯酶的革兰氏阴性菌引起的严重感染,这两种抗生素都非常有效,且优于同类药物[25-27]。同时,阿维巴坦也有一个缺点,即在治疗由牛型碳青霉烯酶产生者引起的感染过程中,耐药性会迅速形成[28]。
第二类能够抑制某些碳青霉烯酶的化合物是硼酸衍生物。属于这一类的伐博巴坦(Vaborbactam)已被授予作为美罗培南/伐博巴坦联合制剂的一部分,用于医学用途[29]。
然而,已批准的受保护β-内酰胺类抗生素种,没有一种对金属-β-内酰胺酶产生者起作用。受保护的抗生素氨曲南/阿维巴坦(avibactam)的开发具有一定前景,目前正在进行第III期临床试验。之所以选择这种组合,是由于氨曲南有其独特的性质。这种抗生素只对革兰氏阴性病原体有活性,很容易被BSBL破坏,但对金属-β-内酰胺酶的水解有抵抗力[30]。在大多数情况下,这类细菌除了碳青霉烯酶之外,还会产生能够破坏氨曲南的β-内酰胺酶(BSBL)和其它β-内酰胺酶,因此不能使用氨曲南来治疗由这些酶的产生者引起的感染。作为联合用物的一部分,阿维巴坦可保护氨曲南免于水解。
一些具有二氮双环辛烷性质的化合物(例如唑巴坦(zidebactam))不仅具有抑制性抗菌活性,还具有内在抗菌活性,目前正处于临床研究或临床研究的早期阶段,因此,我们认为它们是非常有前景的化合物。
环状硼酸衍生物QPX7728具有广谱的丝氨酸和金属-β-内酰胺酶抑制活性[31]。该化合物正在进行临床前研究。
一种全新的抗生素头孢地罗(cefiderocol)的问世带来了一定的前景[32,33]。该化合物是一种混合分子,由一种类似头孢他啶和头孢吡肟的头孢菌素组成,具有丝氨酸和金属-β-内酰胺酶的抗性,具有儿茶酚胺侧链。儿茶酚胺片段能够有效结合细胞外环境中的铁离子,并通过活性铁运输系统在细菌细胞内运输所产生的复合物。这种作用机制被称为"特洛伊木马"策略。然而,对头孢地罗临床疗效的临床研究结果并不像体外数据那样令人印象深刻;在对照临床试验中,该抗生素的疗效并不优于粘菌素[34]。
因此,应该认识到,尽管开发了克服与碳青霉烯酶产生相关的耐药性的药物方面取得了进展,但是该问题远未解决,迫切需要新的抗生素。如上所述,开发新的受保护β-内酰胺这类药物应被视为一个有希望的方向。
本发明的目的在于开发一种抗菌药物,用于治疗因产生碳青霉烯酶而对大多数抗菌药物(包括碳青霉烯类抗生素)产生耐药性的革兰氏阴性菌引起的严重感染。
开发所要求保护的组合物的基础是发现所包含的组分对产生碳青霉烯酶的革兰氏阴性细菌之间具有协同作用。
因此,该技术结果体现了比阿培南和阿维巴坦(aviabactam)对产生碳青霉烯酶的革兰氏阴性菌的协同作用,即显示了试剂(制剂)中两种组分作用的超强整体作用效果。
由于开发了一种联合抗菌制剂,解决了上述任务,该制剂包括碳青霉烯类抗生素比阿培南和重氮双环辛烷类β-内酰胺酶抑制剂阿维巴坦。
所要求保护的组合制剂的新颖之处在于组合制剂中特定组分的选择。在现有的文献中,没有发现与本发明类似的组合制剂的使用报告。
比阿培南是碳青霉烯类抗生素,用于肠胃外使用,与亚胺培南和美罗培南相比,对人类脱氢肽酶-1(DHP-1)具有更强的抗药性,这是由于比阿培南在C1位置存在ip-甲基。比阿培南对多种有氧革兰氏阳性菌、革兰氏阴性菌和厌氧细菌具有杀菌作用,包括肠杆菌目、假单胞菌、拟杆菌和不动杆菌的代表细菌,包括对氨基糖苷类、氟喹诺酮类和头孢菌素类其他抗生素类产生耐药性的细菌。与其他碳青霉烯类相比,比阿培南对金属-β-内酰胺酶碳青霉烯酶的水解表现出更强的抗性。
比阿培南和其他β-内酰胺类抗生素一样,能抑制构成细菌细胞壁的蛋白(肽聚糖)的合成,导致细菌细胞死亡。
比阿培南对各种青霉素结合蛋白(PBPs)具有很高的亲和力:大肠杆菌和铜绿假单胞菌的PBP2、PBPZ和PBP4。比阿培南具有明显的抗生素后效应(即,在药物浓度低于对革兰氏阳性和革兰氏阴性细菌的MIC值后抑制微生物生长)。
对比阿培南产生耐药性的机制包括:激活从细菌细胞环境中清楚抗生素的活性外排系统、破坏将抗生素转运到细胞中的孔蛋白通道的结构、破坏PBPs的结构以及某些β-内酰胺酶的水解作用。
通过临床经验证实了对以下病原微生物的有效性:革兰氏阳性需氧菌-葡萄球菌属(除MRSA外)、链球菌属(包括肺炎链球菌)、肠球菌属(粪肠球菌除外);革兰氏阴性需氧菌-莫拉菌属、大肠杆菌、枸橼酸杆菌属、克雷伯氏菌属、肠杆菌属、沙雷氏菌属、变形杆菌属(Proteus spp.)、流感嗜血杆菌、铜绿假单胞菌、不动杆菌属;革兰氏阳性厌氧菌-消化链球菌属(Peptostreptococcus spp.);革兰氏阴性厌氧菌-拟杆菌属、普雷沃菌属、梭杆菌属。
阿维巴坦(Avibactam)是一种已知的β-内酰胺酶抑制剂,目前与头孢他啶联合销售,用于治疗革兰氏阴性细菌感染。通过创造一种治疗由产生碳青霉烯酶的多重耐药细菌引起的感染性疾病的方法来实现技术效果,该方法是将比阿培南和阿维巴坦以4:1至1:2的比例混合使用,现对本发明的实施方式进行详细描述。
本发明的作者致力于创造一种用于治疗由产生碳青霉烯酶的多重耐药细菌引起的感染性疾病的方法,并对所得产品的有效性进行了评价。
阿维巴坦是一种已知的β-内酰胺酶抑制剂,目前与头孢他啶联合出售,用于治疗革兰氏阴性细菌感染。
实施例1
表1(见下文)显示了对声称的复方制剂和俄罗斯联邦用于治疗严重医院感染的抗生素的活性进行比较评估的结果。研究对象包括对至少一种碳青霉烯类有耐药性并能产生俄罗斯联邦最常见的碳青霉烯酶的克雷伯菌属临床分离物。如表1所示,所有分离菌株均被认为具有多重耐药性。
为了评估抗菌活性,根据《确定微生物对抗菌药物敏感性的方法指南》(MUK4.21890-04)以及欧洲抗菌药物敏感性测试委员会(EUCAST)的建议,通过肉汤微稀释法测定最低抑菌浓度(MIC)值www.eucast.org。
我们使用实用的敏感性标准对各种抗生素组合的抗菌活性进行了比较评估,以预测抗生素及其组合的临床疗效。目前,最低抑菌浓度(MIC)值被用作此类标准,可将感染性病原体分为以下敏感类别之一:"敏感"(S)、"中等"(I)或"耐药"(R)。如果感染性病原体被归类为"敏感",疾病最有可能的结果是痊愈;如果被归类为"耐药",最有可能的结果是治疗失败;如果被归类为"中等",治疗结果不确定。
为了评估组合物的活性,使用了比阿培南和阿维巴坦物质,将其溶解在蒸馏水中并用于制备具有不同组分比例的混合物。不使用另外的稳定剂或填料。
根据欧洲抗菌药敏感性测试委员会(EUCAST)的建议,在使用恒定浓度的阿维巴坦(4.0μg/mL)和比阿培南系列稀释液来评估联合用药的敏感性时,得出了上述结果。
表1比阿培南/阿维巴坦和制剂对克雷伯氏菌属多重耐药分离物的活性比较。
与比阿培南-阿维巴坦复方制剂的主要成分、用于治疗严重感染的基础药物美罗培南、新的受保护的β-内酰胺头孢曲松/阿维巴坦,以及正在进行第三阶段临床试验中有前景的药物氨曲南/阿维巴坦相比,所述药物的详细评估结果如图1和2所示,以及表2和表3也显示了对比药物的MICs分布情况。
通过对这些药物进行比较研究,发现所要求保护的组合药物针对产生NDM型碳青霉烯酶的临床分离物表现出最高水平的活性(图1)。图1显示了与比阿培南-阿维巴坦复方制剂的主要成分以及对比药物美罗培南和头孢曲松-阿维巴坦相比,所要求保护的组合药物的MIC值偏低。MIC分布性质的差异表现为灵敏度水平的差异。表2显示了所要求保护的组合药物对产生NDM型碳青霉烯酶的多重耐药性菌株的敏感性百分比最高。应注意的是,目前尚未制定用于氨曲南-阿维巴坦的敏感性标准。
在比阿培南中添加阿维巴坦会导致MIC值向较低值移动,并增加敏感分离物的比例,这表明这两种化合物之间存在协同作用。协同作用的机制目前是未知的,但是可以认为有三种潜在机制:阿维巴坦对染色体和质粒丝氨酸β-内酰胺酶的抑制作用,阿维巴坦对NDM型碳青霉烯酶的轻微抑制能力及其轻微的内在抗菌活性。就针对NDM型碳青霉烯酶产生者的活性而言,所要求保护的组合与氨曲南/阿维巴坦组合相当。
表2产生NDM型碳青霉烯酶的多重耐药抗性克雷伯氏菌对所要求保护的组合和制剂的耐药性比较(对应于图1中呈现的数据)。
抗生素 | %敏感 | %中等 | %耐药 |
比阿培南-阿维巴坦 | 93.7 | 6.3 | 0 |
比阿培南 | 87.4 | 12.6 | 0 |
氨曲南-阿维巴坦 | - | - | - |
头孢他啶-阿维巴坦 | 6.3 | 6.3 | 87.4 |
美罗培南 | 6.2 | 50 | 43.8 |
所要求保护的组合还表现出对OXA-48型碳青霉烯酶生产者的最高活性(图2)。图2显示了与比阿培南以及对比药物美罗培南和头孢曲松-阿维巴坦相比,所要求保护的组合药物的MIC值偏低。MIC分布的性质的差异表现为敏感性水平的差异。表3显示所要求保护的组合对产生OXA-48型碳青霉烯酶的多重耐药菌株的敏感性比例最高。就敏感分离株的比例来看,该组合与头孢曲松-阿维巴坦组合相当,但就在MIC分布的性质方面,它明显超过了氮曲南/阿维巴坦组合。
表3产生OXA-48型碳青霉烯酶的多重耐药克雷伯氏菌对要求保护的组合和制剂的耐药性比较(对应于图2中呈现的数据)。
抗生素 | %敏感 | %中等 | %耐药 |
比阿培南-阿维巴坦 | 100.0 | 0.0 | 0.0 |
比阿培南 | 34.8 | 56.5 | 8.7 |
氨曲南-阿维巴坦 | - | - | - |
头孢他啶-阿维巴坦 | 100.0 | 0.0 | 0.0 |
美罗培南 | 8.7 | 4.3 | 87.0 |
该组合对同时产生两种碳青霉烯酶的分离物(OXA-48+KPC-2)表现出活性。
该组合中各组分比例的测定表明,比阿培南和阿维巴坦的比例为4:1时,开始显现出明显的协同作用,当阿维巴坦的比例增加至1:2时,协同作用增加,但是进一步增加并不会导致更高的协同作用。对于OXA-48和KPC型的碳青霉烯酶生产者,观察到比阿培南和阿维巴坦之间的协同作用最显著。
表4不同比例的比阿培南和阿维巴坦组合活性的比较评价结果。
因此,通过以4:1至2:2的比例制造比阿培南和阿维巴坦的混合物,解决了制造一种对产生俄罗斯联邦最常见类型碳青霉烯酶(OXA-48、KPC和NDM)的多重耐药革兰氏阴性菌具有活性的药物的任务。
实施例2
为了证实所要求保护的药物的有效性,对产生碳青霉烯酶的多重耐药性细菌引起的小鼠实验性感染进行了研究。以产生碳青霉烯酶NDM-1的肺炎克雷伯氏菌N144作为产生碳青霉烯酶的细菌。
实验中使用的是白发近交系小鼠。动物经腹腔感染。感染后12小时开始用药,共计6次,每次用药间隔12小时。所使用的比阿培南/阿维巴坦比例分别为5:1、4:1、3:2、2:1、1:1、1:2、1:3。
为了进行比较,分别使用了比阿培南和美罗培南。数据如表5所示。
表5。比阿培南/阿维巴坦对小鼠实验性感染的保护效果
从所呈现的数据可以看出,在受感染的动物身上进行的实验证实了所提出的用于治疗由产生碳青霉烯酶的多重耐药性细菌引起的感染性疾病的有效性,这种药物是比阿培南和阿维巴坦以4:1至1:2的比例混合制成。
附图说明
图1为比阿培南/阿维巴坦和对照药物对产生NDM型肺炎克雷伯氏菌碳青霉烯酶的MIC分布。
图2为比阿培南/阿维巴坦和对照药物对产生OXA-48型肺炎克雷伯氏菌碳青霉烯酶的MIC分布。
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Claims (1)
1.一种用于治疗由多种耐药细菌引起的感染性疾病的试剂,包括产生碳青霉烯酶的细菌,其特征在于,所述试剂是比阿培南和阿维巴坦以4:1至1:2的比例制成的混合物。
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