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产超广谱β-内酰胺酶细菌感染防治专家共识

 

产超广谱β-内酰胺酶细菌感染防治专家共识

产超广谱β-内酰胺酶细菌感染防治专家委员会

超广谱β-内酰胺酶(extended-spectrum β-lactamase,ESBLs)是肠杆菌科细菌对β-内酰胺类抗菌药物产生耐药的主要机制之一,其预防与治疗已成为临床医生需要面对的重要问题1,但国内外缺少相关问题处理的指导性意见。《中华实验和临床感染病杂志(电子版)》编辑部和《医学参考报·感染病学频道》编辑部组织国内部分专家制定本《共识》,以对ESBLs相关问题的处理提供指导。

一、超广谱β-内酰胺酶及相关概念

1β-内酰胺酶及分类:β-内酰胺酶是指细菌产生的能水解β-内酰胺类抗菌药物的灭活酶,是细菌对β-内酰胺类抗菌药物耐药的主要机制。其分类见表1

2.超广谱β-内酰胺酶:细菌在持续的各种β-内酰胺类抗菌药物的选择压力下,被诱导产生活跃的及不断变异的β-内酰胺酶,扩展了其耐受头孢他啶、头孢噻肟、头孢吡肟等第

3代及第4代头孢菌素,以及氨曲南等单环β-内酰胺类抗菌药物的能力,这些新的β-内酰胺酶被称为ESBLsESBLs属于Ambler分类的A类和D类酶,按Bush分类属2be。根据质粒所携带编码基因同源性的不同,ESBLs主要有TEMSHVCTXMOXA型。还有一些少见的ESBLs型别,如PERVEBCMZTLASFOGES等。引起临床感染的产β-内酰胺酶细菌依次为肺炎克雷伯菌、铜绿假单孢菌、大肠埃希菌、阴沟肠杆菌等。

二、产ESBLs细菌感染的流行因素及发展趋势

1982年在英格兰首先发现产ESBLs克雷伯菌后,产ESBLs细菌的流行在世界各地广泛报道。ESBLs主要存在于临床分离的革兰阴性杆菌,其中又多见于肠杆菌科细菌2-4。在肠杆菌科细菌中以大肠埃希菌和克雷伯菌最为常见,克雷伯菌包括肺炎克雷伯菌和产酸克雷伯菌。其他常见产ESBLs细菌有产气肠杆菌、变形杆菌、沙门属菌、阴沟肠杆菌、粘质沙雷菌、铜绿假单胞菌、不动杆菌属等。

各个国家和地区产ESBLs细菌的发生率明显不同。日本、荷兰等国家产ESBLs细菌的发生率很低,而法国、印度等国家产ESBLs细菌的发生率很高,可有高达50%以上的克雷伯菌属的细菌产生ESBLs,而且具有较严重的耐药性。我国大陆不同研究者报告的产ESBLs细菌发生率各有不同,大肠埃希菌发生率大约在40%,肺炎克雷伯菌发生率更低一些。

ESBLs细菌主要在医院内引起感染和流行,其中60%发生在大型医院,特别是教学医院5-7。产ESBLs细菌不仅引起院内暴发流行,还可以向院外传播,使流行范围扩大。研究显示,重症监护病房、住院日延长(≥7d)、机械通气、导尿管和动脉导管的留置、严重疾病状态(如器官移植)、不适当联合使用抗菌药物或三代头孢菌素、年龄≥60岁等都是导致产ESBLs细菌感染的危险因素。

 

不同型别产ESBLs细菌在全球流行情况差异很大8-10SHA-2SHV-5呈世界流行;TEM-3在欧洲多见;在美国主要是TEM-10TEM-12TEM-26CTX-MESBLs主要分布于东欧、南美和日本以及远东地区;北美、亚洲和欧洲仍以TEM型和SHV型产ESBLs细菌最为多见。总体上CTX-M型呈逐渐增多趋势,墨西哥,新加坡、泰国、韩国等国家的报道增加。目前我国发现的产ESBLs细菌以CTX-M型为主,SHV型次之,TEM型少见,但因不同省市、不同研究,其报告比例各不相同4.11

三、产ESBLs细菌的实验室检查

临床分离到革兰阴性杆菌,尤其是大肠埃希菌和克雷伯菌等,均应检测是否产ESBLs。出于对流行性、治疗和感染控制方面的考虑,应该把从尿中分离的所有细菌进行ESBLs筛选。推荐先做初筛试验,如初筛试验阳性,再做表型确证试验。对ESBLs阳性细菌,可以进一步研究分析,做蛋白分析试验和基因诊断,以确定ESBLs分型,并发现新的ESBLs

1.初筛试验:纸片扩散法、肉汤稀释法采用其中一种方法,选用头孢泊肟、头孢他啶、氨曲南、头孢噻肟或头孢曲松至少2种,根据药敏试验结果来推测菌株可能产ESBLs细菌。这些方法简单易行,但准确性差、易导致假阴性,只能作为ESBLs的初筛试验,还需进一步做确证试验。

2.表型确证试验:对初筛试验结果提示可能产生ESBLs的细菌,需要做表型确证试验。

纸片扩散法和肉汤稀释法:确证试验需要同时使用头孢噻肟和头孢他啶,单独和联合克拉维酸的复合制剂进行检测。纸片扩散法中2种药物任何一种在加克拉维酸后,抑菌环直径与不加克拉维酸的抑菌环相比增大值≥5MM时,判定为产ESBLs细菌;肉汤稀释法中,与克拉维酸联合的药物MIC相对单独药物的MIC差值≥3个倍比稀释度,判定为产ESBLs细菌。

上述初筛和确证试验方法是目前临床实验室常用方法,此外,还有双纸片扩散法、三维扩散法、头孢硝噻吩竞争分析试验、E-test法及自动化仪器药敏检测法等12

3ESBLs蛋白质分析:(1)等电聚焦电泳:将临床分离菌中粗提的未知ESBLs进行等电聚焦电泳,测定其等电点(pI),与已知酶的等电点进行比较,具有同一等电点的酶可能为同一种酶。如未知酶的等电点与所有的已知ESBLs的等电点不同则可能为一种新的ESBLs。等电聚焦电泳是一种直接而客观的方法,但由于酶的等电点相同或相近,大多难以单独用等电聚焦电泳来进行区别,与其他方法联合应用可提高分辨率。(2)氨基酸序列分析:测定未知酶的氨基酸序列,与已知酶的序列进行比较,是一种准确的方法,同时可发现新的酶,并可更好地了解酶的结构与功能的关系以及酶的衍生情况。本方法繁杂耗时、条件要求高,只限于研究使用。

4ESBLs基因检测:(1)聚合酶链反应(PCR):提取待测菌的DNA,作为扩增模板,采用已知标准酶基因的特异性寡核苷酸引物,进行体外循环扩增,结果如为阳性说明有已知ESBLs的产酶基因。其他方法还有DNA-DNA探针杂交、PCR产物限制性酶切片段多态性分析(PCR-RFLP)等。这些方法灵敏度高,但无法发现新的ESBLs的基因。(2)核苷酸序列分析:将产酶基因(PCR产物、克隆片段等)进行核酸序列分析,分析结果与已知的产ESBLs基因进行比较,发现相同的ESBLs基因或新的ESBLs基因,此方法精确度高,且可能发现新的ESBLs基因以及了解基因突变产生衍生酶的情况。

四、产ESBLs细菌感染的抗菌治疗

(一)产ESBLs细菌感染的治疗原则13-15

1.去除产ESBLs细菌产生的诱因。包括及时拨出各种侵入性导管、尽量缩短住院时间、严格抗菌药物的使用原则等,同时应防止产ESS细菌的医院内扩散。

2.产ESBLs细菌对各种酶抑制剂复合制剂和碳青霉烯类抗菌药物敏感性较高。推荐使用的抗菌药物包括碳青霉烯类、头霉素类、酶抑制剂复合制剂等,也可以根据药敏试验和病情选择氨基糖苷类抗菌药物、氟喹诺酮类与上述抗菌药物联合治疗。具体用药时应关注到如下因素:(1)抗菌药物临床应用指征及目前关于药物的首选与次选的推荐意见;(2)已经使用的抗菌药物的临床疗效及更换药物后的临床表现;(3)本院流行细菌耐药性的流行情况;(4)减低耐药性出现的策略;(5)抗菌药物的价格。

3.对产ESBLs细菌,青霉素类和头孢菌素均耐药。即使体外试验对某些青霉素类、头孢菌素敏感,临床上也应视为耐药,原则上不选用。

4.应该注意到,产ESBLs细菌可以在治疗过程中发展而来。对最初分离敏感的细菌,经(34)d三代头孢菌素的治疗后,有可能发展为耐药,因此对重复分离菌株应重复进行药敏试验。

2010年美国临床和实验室标准化研究所(CLSIM100-S20版《抗菌药物敏感性试验执行标准》中,头孢唑林、头孢噻肟、头孢唑肟、头孢曲松、头孢他啶和氨曲南的判读折点发生改变。新折点的优点在于,临床医生可以直接根据新折点得出的药敏试验结果选择用药,而不需要人为改变药敏结果。

(二)治疗产ESBLs细菌感染的抗菌药物及使用的推荐意见16-18

1.碳青霉烯类:碳青霉烯类对产ESBLs细菌敏感性很高,临床疗效显著,在严重感染或其他抗菌药物治疗疗效不佳时,可选择碳青霉烯类抗菌药物。对可能的产ESBLs细菌的社区感染、院内感染如重症监护室的呼吸机相关肺炎,均可经验性使用碳青霉烯类抗菌药物治疗。药物包括亚胺培南/西司他丁钠、美罗培南、帕尼培南、厄他培南、多尼培南等。美罗培南、帕尼培南不易发生神经系统的不良反应,可用于产ESBLs细菌引起的中枢神经系统感染。目前尚无确切临床资料说明碳青霉烯类与其它抗菌药物联合应用的疗效是否优于碳青霉烯类单独应用,但大多临床医生倾向于运用碳青霉烯类联合氨基糖苷类治疗产ESBLS细菌引起的严重感染。

2β-内酰胺类/β-内酰胺酶抑制剂复方制剂:产ESBLs细菌对β-内酰胺类抗菌药物联合克拉维酸、舒巴坦或他唑巴坦的复方制剂较为敏感。此类药物可首选用于产ESBLs细菌所致的轻度至中度感染,但由于β-内酰胺类/β-内酰胺酶抑制剂复方对产ESBLs细菌的临床疗效不够理想,对产ESBLs细菌严重感染的患者,不宜作为首选药物。在已上市的β-内酰胺类/β-内酰胺酶抑制剂复方中,以头孢哌酮/舒巴坦和哌拉西林/他唑巴坦的抗菌作用较强。应该注意,当细菌产生大量β-内酰胺酶或同时伴有外膜蛋白丢失时,β-内酰胺类/β-内酰胺酶抑制剂复方的抗菌活性也会降低。

3.头霉素类:体外研究显示,头霉素类抗菌药物对于产ESBLs细菌具有良好的抗菌作用,可以作为产ESBLs细菌的次选药物,也可以与氨基糖苷类抗菌药物等联合使用。头霉素类药物包括头孢美唑和头孢西丁。

需要注意到是,头霉素类易诱导细菌产生诱导酶(AmpC酶),从而出现耐药。如果细菌同时有膜蛋白缺失也可引起细菌对头霉素类耐药。

4.第三、四代头孢菌素:不同型别ESBLs对三代头孢菌素的水解能力各不相同,体外实验也可能显示产ESBLs细菌对第三代头孢菌素敏感,但临床上使用三代头孢菌素治疗产ESBLs细菌感染的疗效很差。第四代头孢菌素对ESBLs的稳定性高于第三代头孢菌素,但仍能为ESBLs不同程度的水解,因此,不管体外试验结果如何,所有的产ESBLs细菌均应视为对第三、四代头孢菌素耐药。

5.其他抗菌药物:氨基糖苷类抗菌药物可作为产ESBLs细菌严重感染时的联合用药之一。喹诺酮类抗菌药物可用于治疗产ESBLs细菌引起的轻、中度感染(如尿路感染),但产ESBLs细菌对喹诺酮类的耐药性不断增加,限制了喹诺酮类药物在产ESBLs细菌感染中的应用。研究显示,替加环素(Tigecycline)对产ESBLs细菌有较好疗效,磷霉素对产ESBLs大肠埃希菌所致的复杂性或非复杂性下尿路感染有效率可达93.8%,呋喃坦丁也可用于大肠埃希菌、变形杆菌等引起的急性尿路感染。

(三)产ESBLs细菌的抗菌药物治疗的推荐方案19-22

1.肠杆菌科:产ESBLs细菌感染的研究中,对肠杆菌科的大肠埃希菌、克雷伯菌的研究最多,其产ESBLs率也最高。目前实验室对培养得到的大肠埃希菌、克雷伯菌常规做ESBLs检测。参考2010年(CLSIM100-S20版《抗菌药物敏感性试验执行标准》,对产ESBLs肠杆菌科细菌(主要是大肠埃希菌、克雷伯菌、阴沟肠杆菌),应结合药敏试验结果和临床表现严重性,确定抗菌药物治疗方案。

对轻至中度感染患者,首选复方β-内酰胺类/β-内酰胺酶抑制剂(药物包括阿莫西林/克拉维酸、氨苄西林/舒巴坦、哌拉西林/他唑巴坦、替卡西林/克拉维酸等)。次选氨基糖苷类与头霉素类抗菌药物联合治疗(药物包括阿米卡星、妥布霉素、头孢西丁、头孢美唑等)。治疗效果不佳者,换用碳青霉烯类抗菌药物(药物包括亚胺培南、美罗培南、厄他培南、帕尼培南)。

对严重的产ESBLs肠杆菌科细菌感染,以及医院发生产ESBLs肠杆菌科感染,可以首选碳青霉烯类抗菌药物或联合治疗方案。

2.铜绿假单胞菌:对产ESBLs铜绿假单孢菌的抗菌药物治疗,可以选择复方β-内酰胺类/β-内酰胺酶抑制剂治疗(推荐药物为哌拉西林/他唑巴坦、替卡西林/克拉维酸)、氨基糖苷类联合头霉素类抗菌药物(推荐药物阿米卡星、妥布霉素、头孢西丁、头孢美唑等),或碳青霉烯类抗菌药物(推荐药物为亚胺培南、美罗培南、帕尼培南)。

铜绿假单胞菌感染多为医院感染,多重耐药,产ESBLs并非其主要的耐药机制。专家组将对铜绿假单胞菌感染制作独立的防治方案。

3.不动杆菌属:对产ESBLs不动杆菌属感染,首选碳青霉烯类抗菌药物(推荐药物亚胺培南、美罗培南、帕尼培南),次选氨苄西林/舒巴坦、哌拉西林/他唑巴坦、替卡西林/克拉维酸。对泛耐药不动杆菌感染的治疗,可用多粘菌素。与铜绿假单胞菌一样,不动杆菌属感染多为医院感染,多重耐药,产ESBLs并非其主要的耐药机制。专家组将对不动杆菌属感染制作独立的防治方案。

五、产ESBLs细菌感染的预防

ESBLs引起的细菌耐药性可导致患者的住院时间延长,治疗费用增加,病死率升高。产ESBLs细菌感染的流行也引起医院感染的增多及传播,增加了临床治疗的难度。因此,产ESBLs细菌的预防非常重要。

1.加强检测:产ESBLs细菌的流行和感染的防治,首先要加强对产ESBLs细菌的检测23。实验室检测有助于明确产ESBLs细菌感染,便于采取消毒隔离措施。检测ESBLs以双纸片法、CLSI表型确证试验(纸片法)较为简便、准确,可作为临床微生物的常规检测方法。在分子流行病学的调查中,常采用脉冲电泳(PFGE)和质粒指纹图谱分析分别检测产酶细菌的克隆传播和耐药基因的水平传播。住院患者中常规监测产ESBLs细菌定植,可能有助于产ESBLs肠杆菌科的预防和管理。肺炎克雷伯菌产生的ESBLs可以造成新生儿病房的耐药率增高。实验者每月收集病房内空气培养、早产儿保育箱内培养、药车及洗涤槽的培养,以及医护人员的手培养均可以发现耐药菌的存在。

2.合理使用抗菌药物:有证据表明,不适当的抗菌治疗是产ESBLs细菌的独立预测因素,包括不必要的延长抗菌药物治疗、不恰当的给药剂量、不合理的给药剂型、错误的给药时间以及不适当的预防性治疗等24-26。第三代头孢菌素经验性用药可导致更多产ESBLs细菌出现,从而引起产ESBLs细菌的流行。由于编码ESBLs的质粒往往同时还携带其它的耐药基因,因此氨基糖苷类等其它抗菌药物也需控制使用。抗菌药物控制策略必须强制执行以减少细菌的耐药。具体措施包括严格抗菌药物的使用指征,尽量少用第三代头孢菌素类及青霉素类抗菌药物。一项NICU中产ESBLs细菌感染的经验性治疗表明,从头孢噻肟联合万古霉素转变为妥布霉素联合万古霉素可降低产ESBLs细菌感染。

3.加强隔离和消毒:对产ESS细菌感染者应隔离治疗。医院患者和工作人员的皮肤可以有耐药菌寄居,这些菌可在院内传播,也可传播到社区。为控制耐药菌的发生和传播,医护人员应多使用一次性手套和加强洗手,减少医院内交叉感染;住院患者应尽量缩短住院时间,减少侵袭性操作以及加强医疗器械的消毒灭菌。

六、结语

ESBLs细菌在世界范围内广泛分布,各国家和地区中细菌产生ESBLs的类型和产ESBLs细菌的发生率有显著差异。ESBLs的种类繁多且不断增加,各种ESBLs的特性有所不同。产ESBLs细菌可通过产酶细菌的克隆传播(垂直传播)和产酶基因的水平传播(质粒转移、编码基因转座等)在医院内造成暴发流行。产ESBLs细菌一般为多重耐药株,产ESBLs细菌感染的治疗已经成为临床上的一大难题,故产ESBLs细菌感染的防治有着重要意义。

专家委员会(按拼音顺序):陈宝敏、陈志海、成 军、

黄东生、李兴旺、李 旭、林佳佳、刘景院、刘晓清、卢洪洲、卢联合、倪语星、宁琴、曲芬、沈叙庄、斯崇文、谭德明、唐云、王辉、王 宇、于岩岩、肖永红、徐英春、杨道峰、俞云松、赵辉、赵红心、赵敏、郑波、朱德妹

致谢:非常感谢陈志海教授在共识相关资料搜集、整理及起草过程中所作出的贡献。

 

 

 
来源:北京顺义区医院      时间:2011-9-8 16:38:20      浏览次数:15389
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