Mysterious Klebsiella Outbreak Traced by Genome Sequencing

Ricki Lewis, PhD

August 22, 2012

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.

Klebsiella pneumoniae (magnified 1000x). Source: Image courtesy of Adrian Zelazny.

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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