美国微生物学会于6月26日网络新闻及7月学会会刊“微生物”（Microbe）杂志就抗生素抗药性研究方面的又一重大突破发布新闻。最新研究表明抗生素抗药性的快速增长和口服抗生素存在相关性，这项发现为人类通过改变抗生素给药方式来减少细菌对抗生素抗药性的产生带来了新希望。该论文的网络版已先于8月号美国微生物学会杂志“抗微生物制剂和化疗”(Antimicrobial Agents and Chemotherapy)发表。
“在过去40多年时间里，几剂青霉素曾经就足可以治愈原本致命的细菌感染，”主持该项研究的王华教授说。但从八十年代起，抗生素抗药性的快速传播使一度威力无比的抗生素失去了固有的功效，导致越来越多的病人重又受虐于细菌感染，甚至于弊命。
王教授任职于美国哥伦布市俄亥俄州立大学食品与科技系，也是该校微生物系及中国复旦大学生命科学院的兼职教授。王教授还曾担任美国食品科技协会生物工程分会主席，美国微生物学会食品分会主席，是国际著名食品安全及微生物学专家，在食品安全及人类健康领域做出了突出贡献。在过去的八年多时间里，王教授领导的团队已在许多即食食品中发现了巨大的由非致病菌所携带的抗药性基因库，表明普通食品可以成为传播抗药性细菌的载体。一些传统意义上的发酵及益生菌也可能会携带抗药性基因并加速其在微生物生态体系中的传播。美国微生物学会曾于2007年5月23日就这一重大发现专门召开全球新闻发布会。王教授团队随后并进一步发现抗药性肠道菌群在婴儿出生后就有快速增长，即使这些婴儿从来没有使用过抗生素。这些结果表明宿主（人或动物）肠道可能在抗生素抗药性增殖传播中起到重要作用。
在这项新近发布的研究中，研究人员给实验老鼠喂食带有特定抗药基因的肠球菌及大肠杆菌， 再通过口服及针剂注射的方式给予四环素或氨苄青霉素。 口服抗生素导致老鼠粪便中抗药性基因库的快速增长。相比而言，由注射给予同剂量同种抗菌素，其抗药性的产生明显缓慢或较少。研究者们同时发现，无论是否给予抗生素或以何种形式给予抗生素，在没有喂食过带有特定抗药基因细菌的对照组老鼠粪便中都没有检测到特定的抗药性基因库。该结果表明如果没有先前抗药性细菌由口鼻及食源引入，短期的抗生素治疗并不会造成抗药性基因的快速产生。由此，该实验也证明了食品中抗药性细菌污染的危害。
抗生素抗药性近年来已对人类生命财产造成了重大危害。在美国，每年至少有9万人直接死于医源性致病菌的感染，其中大部分致病菌具有抗药性。更多的慢性病患，如许多癌症，艾滋病等病人也最终死于无药可治的抗药性细菌感染。长期以来国际上一直认为抗生素治疗及其在畜牧业中的应用是造成抗药性的源头，因此欧美各国近年来推崇严格控制处方抗生素的使用，不仅是一般的感冒，甚至一些创伤性手术后都避免使用抗生素。但是抗药性问题并没有得到很好解决，相反由于缺乏抗生素早期干预造成继发性或慢性感染的例子时有发生，对病人健康造成严重后果。
抗生素应用已有很长的历史，包括在第二次世界大战期间大量用来治疗伤员。抗药性细菌很早就有报道，但并没有对治疗造成大规模威胁。早期抗生素治疗一般都是通过静脉或肌肉注射。从80年代起口服抗生素制剂开始推广成为主流。抗生素在畜牧业上的应用也大多通过饲料或饮水给药。人和动物肠道是菌群生长最密集的地方。由于口服抗生素直接和肠道中大量菌群接触，势必造成抗药性细菌的快速增殖。这些抗药性细菌然后又会通过粪便经水及土壤进入环境体系，再由食物，水源，或环境接触重新进入消化系统开始新一轮增殖循环。而注射则减少了肠道细菌和抗生素的直接接触，所以会减少抗药性的产生。由于几十亿人和动物每天产生的带有大量抗药性细菌的粪便对环境抗药基因库最具影响力，口服抗生素可能是造成抗药性快速增长最重要的危险因子之一。这一崭新的理论观点不仅得到上述实验数据支持，而且也非常契合历史上从八，九十年代起抗药性大幅增长的时间点。另外，英国帝国大学科学家曾报道抗生素应用会导致肠道菌群失去多样性。而不正常的肠道菌群和一些非传染性疾病，如自身免疫失调及II型糖尿病的发生有关联。口服抗生素的影响可能也不能忽视。
王教授团队的上述开创性发现不仅颠覆了传统观念，而且为解决在减灭抗生素抗药性快速增长的同时不因噎废食限制必要的抗生素治疗干预提供了理论依据及客观可行的方向。可以预见这一发现会对全球细菌感染性疾病的治疗规则及畜牧业生产产生重大及长远的影响。
王教授的助手张陆博士从2008年加入研究团队后是婴儿及动物模型研究项目的主要实施者。由中国留学基金会资助的在读博士生黄莹及周旸，及俄州大公共卫生学院Tim Buckley教授也参与了这项研究。
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Public release date: 26-Jun-2013
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Contact: Jim Sliwa
jsliwa@asmusa.org
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American Society for Microbiology
Antibiotics: Change route of delivery to mitigate resistance
New research suggests that the rapid rise of antibiotic resistance correlates with o ral ingestion of antibiotics, raising the possibility that other routes of administration could reduce the spread of resistance. The manuscript appears online ahead of print in the journal Antimicrobial Agents and Chemotherapy.
"For more than 40 years, a few doses of penicillin were enough to take care of deadly bacterial infections," says Hua Wang of the Ohio State University, Columbus, a researcher on the study. But since the 1980s, antibiotic resistance has been spreading rapidly, disabling once-powerful agents, leaving increasing numbers of patients to suffer, and even to die.
In earlier research, the investigators found a large cache of antibiotic resistance genes carried by nonpathogenic bacteria in many ready-to-consume food items. They also reported rapid development of resistant bacteria in infants who had not been exposed to antibiotics, shortly after birth, suggesting the gastrointestinal tract played a critical role in spreading resistance.
In the new research, the researchers inoculated lab mice with either Enterococcus species or Escherichia coli carrying specific resistance genes. The mice were then given tetracycline or ampicillin antibiotics, either orally, or via injection. Oral administration of antibiotics resulted in rapid rise of resistance genes as measured in the mice' feces. Resistance spread much less, and more slowly when the mice received antibiotics via injection.
The researchers also found that antibiotic resistance genes were not detectable in mice that had not been inoculated with bacteria containing antibiotic resistance genes, regardless of the route of antibiotic administration.
The human death toll from resistance, Wang says, is much higher than the 90,000 figure provided by the Centers for Disease Control and Prevention. The difference is due to the fact that bacterial infection is often the direct cause of death in many patients with chronic diseases, such as HIV/AIDS and cancer.
Besides resistance, recent work has shown that the use of oral antibiotics can reduce the diversity of the gut flora. Abnormalities of the gut flora are associated with multiple non-infectious diseases, including several autoimmune diseases and type II diabetes, according to Jeremy Nicholson of Imperial College, London, UK. Thus, alternatives to oral administration could likely mitigate these kinds of problems, as well.
Convenient alternatives to oral antibiotics might include transdermal administration via a patch, or other devices, says Wang.
Wang suggests that it should not be surprising that oral administration would abet the spread of resistance genes, since this route, unlike injection, directly exposes the humongous population of gastrointestinal bacteria to antibiotics. The resulting resistant microbes then get transmitted to the environment via the feces. From there, bacteria containing resistance genes once again gain entry to the food supply, via livestock, or via produce that has been exposed to manure from industrial livestock, as well as contaminated waste and soil, in a vicious cycle.
"Revealing this key risk factor is exciting because we have options other than oral administration, including convenient ones, for giving antibiotics," says Wang.
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A copy of the manuscript can be found online at http://bit.ly/asmtip0613c. The paper is scheduled to be formally published in the August 2013 Antimicrobial Agents and Chemotherapy.
Antimicrobial Agents and Chemotherapy is a publication of the American Society for Microbiology (ASM). The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. Its mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.