中华预防医学杂志2018年04期
中华医学会主办。
中华医学会主办。
文章信息
- 李菁 要茂盛
- LiJing,YaoMaosheng
- 空气介质中耐药细菌和耐药基因的研究进展
- State-of-the-art status on airborne antibiotic resistant bacteria and antibiotic resistance genes
- 中华预防医学杂志, 2018,52（4）
- http://dx.doi.org/10.3760/cma.j.issn.0253-9624.2018.04.021
- 引用本文：
-
文章历史
- 投稿日期: 2017-11-30
空气介质中耐药细菌和耐药基因的研究进展
李菁 100871 北京大学环境科学与工程学院
要茂盛 100871 北京大学环境科学与工程学院
要茂盛 100871 北京大学环境科学与工程学院
摘要: 全球正在面临着由于耐药细菌感染和抗菌药物短缺而导致的更多死亡，而其重要的空气传播途径未能受到足够的关注与重视。本文结合最新文献，综述了耐药细菌和基因在不同环境空气介质中的丰度、分布、传播等方面的研究进展，并讨论监测防控的相关措施。耐药细菌和基因在职业暴露场所及其周边空气中的丰度普遍高于普通室内与室外的空气环境。与其他环境介质相比，空气介质蕴含着种类更加丰富的耐药基因，且可以通过附着在空气颗粒物上进行扩散。可通过加强监测、研究其传播机制和生物毒性以及研发病原体快速甄别技术和新型绿色抗菌药物等，有效防控细菌耐药性对人体健康及生态环境的危害。
关键词
:抗菌药;颗粒物;耐药基因;空气传播
State-of-the-art status on airborne antibiotic resistant bacteria and antibiotic resistance genes
State Key Joint Laboratory of Environmental Simulation and Pollution Control, College of Environmental Sciences and Engineering, Peking University, Beijing 100871, China
Corresponding author: Yao Maosheng, Email: yao@pku.edu.cn
Corresponding author: Yao Maosheng, Email: yao@pku.edu.cn
Abstract:The world is facing more deaths due to increasing antibiotic-resistant bacterial infections and the shortage of new highly effective antibiotics, however the air media as its important transmission route has not been adequately studied. Based on the latest literature acquired in this work, we have discussed the state-of-the-art research progress of the concentration, distribution and spread of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in different environmental air media, and also analyzed some future prevention and control measures. The large use of antibiotics in the medical settings and animal husbandry places has resulted in higher abundances of ARB and ARGs in the relevant and surrounding atmosphere than in urban and general indoor air environments. ARGs can be spread by adhering to airborne particles, and researchers have also found that air media contain more abundant ARGs than other environmental media such as soil, water and sediment. It was suggested in this review that strengthening the monitoring, study on spreading factors and biological toxicity, and also research and development on pathogen accurate diagnosis and new green antibiotic are expected to help effectively monitor, prevent and control of the impacts of airborne resistant bacteria and resistance genes on both human and ecologies.
Key words
:Antibiotics;Particulate matter;Antibiotic resistance genes;Aerial transport
全文
动物养殖场是抗生素使用的一个重要场所。研究认为，与动物养殖有关的农业活动是环境中细菌获得耐药性过程的主要贡献者[1 ,34 ]。根据Zhang等[35 ]的研究，2013年中国抗生素的总消耗量为162 000吨，动物养殖产业的使用量占比52%，美国动物养殖产业抗生素使用量则高达82%[36 ,37 ]。因此，已从养殖场及周边空气中广泛检测到耐药细菌[38 ,39 ,40 ,41 ,42 ,43 ,44 ,45 ]。以MRSA为例，Friese等[42 ]研究发现德国27家养猪场内的空气样品中MRSA检出率高达55.6%~85.2%，其浓度受到采样方法的影响，如撞击式采样器采集的MRSA平均浓度为257 CFU/m3，而膜采样器采集的MRSA平均浓度为802 CFU/m3。除了采样器，颗粒物粒径也是空气中耐药细菌检出浓度的影响因素。Ferguson等[45 ]发现养猪场内空气中的MRSA多检出于粒径大于5 μm的颗粒物上，而养猪场周边空气中的MRSA检出于粒径小于5 μm的颗粒物上。对空气中耐药细菌浓度和分布的研究大多是基于培养的方法，而评估耐药基因在空气中的丰度和分布采用的是实时荧光定量PCR技术。Ling等[29 ]在美国科罗拉多州的猪养殖场和奶牛养殖场的空气中均检测到了四环素类耐药基因tetX （100~200拷贝/m3）和tetW （100~400拷贝/m3）。Gao等[46 ]在蛋鸡养殖场和肉鸡养殖场的空气中分别检测到了四环素类耐药基因tetW （10~106拷贝/m3）和tetL （102~106拷贝/m3），虽然两种耐药基因都随着颗粒物粒径的增大丰度增高，但粒径较小的颗粒物（4.32~5.33 μm）中tetL 的丰度较大，粒径较大的颗粒物（5.34~6.38 μm）中tetW 的丰度较大。
在其他职业环境中，如市政污水处理厂（urban wastewater treatment plant, UWTP）每日人均当量的出水中约含109~1012 CFU，其中至少有107~109 CFU的细菌属于获得性耐药[47 ]。因此污水处理厂（wastewater treatment plant, WWTP）的空气环境中耐药细菌和基因的检出近年来也逐渐被报道[48 ,49 ,50 ]。例如，Li等[49 ]在北京的一座污水处理厂内格栅间和曝气池区域的空气样本中检测到磺胺类耐药基因sul2 和可以帮助其进行水平转移的整合酶基因intI1 ，但没有进行定量。高新磊等[50 ]分析了深圳市罗湖区罗芳污水处理厂内的21份空气样本中的四环素类耐药基因（tetC 、tetG 、tetO 、tetX ）、磺胺类耐药基因（sul1 、sul2 ）和大环内酯类耐药基因（ermB 、ermC ），发现不同工艺单元区域空气样本中耐药基因的丰度不同，如曝气池和污泥脱水车间的空气样品中sul1 、sul2 、tetG 和tetX 的丰度较高，范围在102~105拷贝/ng DNA之间。
此外，医院作为人类疾病相关抗生素的主要消耗场所，其空气环境被认为是各种耐药细菌、甚至是多重耐药（multi-drug resistant, MDR）细菌的储藏库[26 ,51 ,52 ,53 ,54 ]。邱玉玉等[53 ]在山东省5所大中型医院的250份室内空气样品中分离出219株金葡菌，其中MRSA 88株，这些MRSA均对青霉素类及头孢曲松耐药，对庆大霉素、红霉素和四环素的耐药率超过90%。Solomon等[54 ]发现在埃塞俄比亚中南部的Wolaita Sodo大学教学医院的室内空气中73.6%~84.6%的常见耐药致病菌（凝固酶阴性葡萄球菌、金黄色葡萄球菌、粪肠球菌和屎肠球菌、不动杆菌属、大肠杆菌和铜绿假单胞菌）表现为多重耐药。足以见得，医院环境已经成为一个滋生耐药细菌及耐药基因的重要温床。
职业暴露场所空气中的耐药细菌和基因会对场所内部和周边的人群健康造成呼吸暴露风险。以MRSA为例，医院获得性MRSA（hospital-acquired MRSA, HA-MRSA）的传播媒介除了医护人员本身（如医护服、医用手套等）及其所使用的医疗用具外[27 ,55 ]，气源传播也被认为是发生MRSA呼吸道感染及创面感染的重要途径[27 ,56 ,57 ]。Zheng等[28 ]利用环介导等温扩增技术（loop-mediated isothermal amplification, LAMP）从呼吸道感染患者的呼出气中检测到了MRSA，证明MRSA可以通过患者的呼出气进行传播。在畜牧业相关的职业暴露场所中，MRSA可以大量存在于感染畜群产生的灰尘中，导致工作人员吸入携带MRSA的灰尘颗粒物而被感染[42 ,58 ,59 ,60 ,61 ,62 ,63 ]。Angen等[63 ]发现在养猪场内工作的志愿者鼻腔内的MRSA浓度与养猪场内空气中的MRSA浓度显著正相关。此外，Laube等[43 ]在德国肉鸡养殖场的肉鸡体内、养殖场土壤、养殖场空气和养殖场下风向50米处的空气中均检测到了基因型完全相同的产ESBL/AmpC酶大肠杆菌菌株。Navajas-Benito等[44 ]在西班牙奶牛养殖场和其周边的空气样本中均检测到了基因型相同的多重耐药大肠杆菌菌株ESTE50。此外，McEachran等[4 ]设计实验发现耐药基因在牛养殖场下风向颗粒物样本中的丰度均显著高出上风向样本约100~4 000倍（P 值<0.002），证明耐药基因可以附着在颗粒物上进行传播。越来越多的研究证实耐药细菌和基因可以通过空气进行扩散并能够在一定时间内保持活性。
抗生素的长期滥用导致了细菌耐药性的增强、超级细菌的出现和日益增多，这些已经或正在严重危及人类健康[
为了评估抗生素滥用对生态平衡和人类健康带来的严重后果，已有学者针对各种地表环境中的耐药细菌和基因传播蓄积等进行了大量研究，如污水处理厂、河流、底泥、养殖场、农田等[
一、耐药细菌在空气中的来源、浓度和分布 除了不同的地表环境介质，包括土壤、水体界面如湖泊、海洋、河流等自然源，部分人为活动如污水处理、畜牧养殖、堆肥发酵等也是空气中细菌的重要来源[
 |
| 图1空气介质中耐药菌及耐药基因排放源、传播及影响 |
在其他职业环境中，如市政污水处理厂（urban wastewater treatment plant, UWTP）每日人均当量的出水中约含109~1012 CFU，其中至少有107~109 CFU的细菌属于获得性耐药[
此外，医院作为人类疾病相关抗生素的主要消耗场所，其空气环境被认为是各种耐药细菌、甚至是多重耐药（multi-drug resistant, MDR）细菌的储藏库[
职业暴露场所空气中的耐药细菌和基因会对场所内部和周边的人群健康造成呼吸暴露风险。以MRSA为例，医院获得性MRSA（hospital-acquired MRSA, HA-MRSA）的传播媒介除了医护人员本身（如医护服、医用手套等）及其所使用的医疗用具外[
二、普通室内与室外空气中耐药细菌和基因的丰度、分布和传播 细菌耐药性问题的棘手之处在于即使在普通室内和室外的空气介质中，耐药细菌和基因也已经逐渐被检测到。Gandolfi等[
可以看出，目前对于空气环境中耐药基因的研究多集中于四环素类或有限的几种基因片段，造成这种情况的主要原因是受限于传统的荧光定量PCR技术。而高通量荧光定量PCR技术可以实现同时对多达上百种抗性基因或多个样品进行定量分析[
关于空气介质中耐药基因的影响因素，Hu等[
三、研究展望 经过多方努力，我国在解决大气污染问题上已经取得了一定进展；但空气中的耐药基因作为新型空气污染物的出现没能得到足够的重视，特别是我国是抗生素使用大国。耐药细菌和耐药基因均能够形成生物气溶胶，不仅能在一定的条件下引起气源感染，对人类的生命健康造成威胁，而且可以通过沉降影响微生态平衡。与其他环境介质相比，空气介质蕴含着种类更加丰富的耐药基因；然而关于其来源、分布和传播机制等的文献报道仍旧匮乏，使得空气生物污染问题被严重低估。综合现有的状况，除了从国家和政府层面上继续加强管理和控制抗生素在畜牧养殖业和医院临床治疗中的使用以外，在未来应对耐药细菌以及耐药基因的相关研究及行动中，特别是在空气介质中的，作者认为如下几点可能需要特别关注，从而可以为有效防控细菌耐药性的扩散、更好地保护人群健康。
1．开展环境中耐药细菌监测： 大力开展对职业环境、室内环境和大气环境空气中耐药细菌和基因丰度和分布的监测工作，获得空气中常见耐药细菌和基因（包括基因转移元件）的清单，同时为建立抗生素使用和空气中耐药细菌和基因的丰度之间的数学模型提供数据基础；此外，目前对于空气中耐药基因的研究，大多没有区分其究竟是来自有活性的宿主细胞，还是裸露游离的DNA分子，这影响了我们对耐药基因在不同环境介质中的扩散机制的理解，在未来的研究中应注意区分。
2．研究细菌耐药和基因传播机制： 利用实验室研究和模拟研究分析耐药细菌和基因的传播机制，如传播距离，以及经过远距离传输后是否还具有生物活性等，是否仍然具有危害性，分析环境因子如气象条件、大气辐射等对耐药细菌和基因传播效率的影响。
3．开展空气中耐药细菌和基因毒理学研究： 利用动物模型等对空气中耐药细菌和基因进行毒理学研究，并深入了解耐药细菌和基因对呼吸道微生态的影响，为建立空气中耐药细菌和基因的风险评估体系和空气耐药微生物浓度标准体系提供数据支持。
4．发展病原体快速、精准的甄别技术： 该技术的发展也是遏制细菌耐药性发展的关键。例如，过去研究人员通过利用生物传感器可以在几分钟内检测到临床患者呼出气中H3N2病毒和H1N1病毒[
5．加大开展新型抗菌药物的研发工作： Ling等[
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