Mysterious Klebsiella Outbreak Traced by Genome Sequencing

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August 22, 2012 — Microbiologists, epidemiologists, and genome researchers teamed up to solve the mystery of how a single patient introduced carbapenem-resistant Klebsiella pneumoniae to a major clinical center and infected 17 others, 11 of whom died.

The outbreak apparently began in June 2011, when a very ill 43-year-old woman was transferred from a hospital in New York City to the National Institutes of Health (NIH) Clinical Center. Three weeks after her discharge from the center, the first patient developed symptoms from the infection. Evan S. Snitkin, PhD, from the National Human Genome Research Institute, Bethesda, Maryland, and colleagues describe the outbreak in an article published online August 22 in Science Translational Medicine.


K pneumoniae is resistant to many antibiotics, flourishes in a hospital environment, survives on the hands of hospital workers, and can remain in a reservoir in the gastrointestinal tracts of asymptomatic individuals, obscuring transmission patterns. The mortality rate for infected patients approaches 50%. In the NIH outbreak, 6 of the 11 deaths were attributed to the bacterial infection.

Standard strain-typing tests such as pulsed-field gel electrophoresis and multilocus sequencing are too limited to usefully subclassify K pneumoniae because 70% of the bacteria are of the same strain. Whole-genome sequencing provides the detail and precision to track the route of infection.

The bacterial genome is about 6 million bases, with 41 known single nucleotide variants (SNVs), which provide points of comparison for an algorithm to reconstruct the spread of the infection. However, bacteria in the index patient mutated during the course of the study.

The researchers used genome sequence and patient trace data to reconstruct events. For the index case, they obtained 6 bacterial isolates from 4 body sites during the patient's 4-week stay at the NIH Clinical Center. They then sequenced the bacterial genomes from the 17 infected patients. Sequence comparisons enabled the investigators to infer possible transmission routes by grouping patients whose sequences could have derived from the index case at the same SNVs.

Two major clusters of patients and 1 individual to whom the infection spread emerged. In 1 cluster, 3 SNVs matched those from the index patient's groin and lungs (bronchoalveolar lavage). Individuals in the other cluster had 3 SNVs from the initial patient's throat. One patient was a mystery, but the researchers found 5 of 1115 patients in the clinical center at the time whose bacterial genomes indicated they could have been "silent transmission vectors."

Next, consideration of epidemiology enabled the researchers to identify a most likely scenario of who infected whom. The analysis also included the nonliving, and 1 patient's infection was traced to a contaminated ventilator.

Genome sequencing of pathogens can complement standard infection control measures, which the clinical staff had implemented, by highlighting people and equipment that can transmit a particular pathogen. The researchers conclude, "Our analysis demonstrates that integration of genomic and epidemiological data can yield actionable insights and facilitate the control of nosocomial transmission."

The study was supported by the National Human Genome Research Institute, NIH Clinical Center Intramural Research Programs, and an NIH Director’s Challenge Award for genome sequencing. The lead author was supported by a Pharmacology Research Associate Training Fellowship from the National Institute of General Medical Sciences. The authors have disclosed no relevant financial relationships.

Sci Transl Med. Published online August 22, 2012. Abstract

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2012年8月22日-微生物学家，流行病学家和基因组的研究人员合作，解决一个病人的主要临床中心介绍了碳青霉烯类耐药肺炎克雷伯菌感染的17人，其中11人死亡的神秘面纱。 的爆发显然是开始于6月2011年，当一个病得很重的43岁女子在纽约市一家医院被转移到美国国立卫生研究院（NIH）临床中心。三个星期后，她出院的中心，第一个病人出现症状的感染。埃文S. Snitkin，博士，美国国家人类基因组研究所，美国马里兰州贝塞斯达市，和他的同事在网上公布，8月22日在“科学-转化医学的文章中描述的爆发。 肺炎克雷伯菌耐对许多抗生素在医院环境中，一夜暴富，医院工作人员手中的生存，并能保持在一个水库在无症状患者的胃肠道的，模糊的传输模式。感染患者的死亡率接近50％。在美国国立卫生研究院的爆发中，有11人死亡6人的细菌感染。 标准应变打字测试，如脉冲场凝胶电泳和多位点测序太有限了有益的细致区别肺炎克雷伯菌，因为70％的细菌是相同的应变。全基因组测序提供了详细和精确跟踪路由感染 的细菌的基因组是大约6万个碱基，41公知的单核苷酸的变种（SNVs），它提供了一种算法来重构感染扩散的比较点。然而，在索引中患者的细菌突变在研究过程中， 研究人员使用的基因组序列和患者跟踪数据来重建事件。对于索引的情况下，他们获得了6个细菌菌株在患者的4个星期的逗留在美国国立卫生研究院临床中心从4个部位。然后，他们感染的17例细菌的基因组测序。序列比较，使调查人员推断可能的传播途径，通过将患者的序列可能来自在同一SNVs中的索引的情况下。 两个主要的患者群和1个别人出现感染扩散。在1簇3 SNVs中匹配，从源头病人的腹股沟和肺支气管肺泡灌洗。在其他集群的个体3 SNVs中，从最初的病人的喉咙。一个病人是一个谜，但研究人员发现了1115例临床中心的时候表示，他们可能是“沉默的传输载体的细菌基因组。” 接下来，考虑的流行病学使研究人员能够确定最有可能的情况下，谁感染了谁。分析也包括无生命的，追查受污染的呼吸机和1例患者的感染 病原体基因组测序的补充标准的感染控制措施，突出人员和设备，可以发送一个特定的病原体，临床医务人员实施了。研究人员得出结论，“我们的分析表明，基因组学和流行病学数据的整合，可以产生可操作的见解和方便的控制院内感染。” 这项研究是由国家人类基因组研究所，美国国立卫生研究院临床中心院内研究计划，和美国国立卫生研究院支持主任基因组测序的科技挑战奖“。支持的主要作者的药理学研究助理的培训奖学金由国家普通医学科学研究所。作者们皆宣告没有相关财务关系。 科学译地中海。线上发表于2012年8月22日