Genome Advance of the Month

Whole genome sequencing used to track infection's transmission path

By Joy Yang
Post-baccalaureate Fellow
Klebsiella pneumoniae

The sequencing of the human genome promised to revolutionize clinical medicine, and our August genome advance is another step in the direction of fulfilling this promise. In June, we covered the publications of the Human Microbiome Project, which emphasizes the beneficial microbes that live in harmony with humans. However, the microbes that loom in hospitals and threaten patients cannot be ignored.

Today, 5 to 10 percent of patients admitted to acute care hospitals acquire an infection. The ability to prevent these infections has been limited by our understanding of how they spread. Tracking the path of infection has traditionally relied on manual inspection of patient records, a process that does not provide definitive proof of the proposed route of transmission. Using whole bacterial genome sequencing to trace the transmission of a hospital-acquired infection is this month's genome advance of the month, a potentially important breakthrough for hospital epidemiology.

When a cluster of antibiotic-resistant Klebsiella pneumoniae infections was detected at the National Institutes of Health (NIH) Intensive Care Unit (ICU) in NIH's Clinical Center, physicians questioned whether there was a link between the first patient diagnosed and the rest of the cases. There had, after all, been a three-week gap between the discharge of the initial patient and the subsequent detection of disease in the next. Evan Snitkin, Ph.D., a postdoctoral fellow in the lab of Julie Segre, Ph.D., at the National Human Genome Research Institute, set out to uncover the transmission path of this infection, and to discover, specifically, whether the first patient was connected to the cluster of infections. Current diagnostic tools failed to provide the needed resolution, so Dr. Snitkin employed whole genome sequencing of the bacterial samples.

The bacterial samples taken from patients 2, 3 and 5 all shared three single nucleotide variants (SNVs) that were the signature of the bacteria present in the first patient's throat sample. The infection was likely transmitted when patients 1 and 3 overlapped in the ICU. Thirteen other patients, with patient 4 at the head of the chain of infection, displayed three SNVs that were the signature of bacteria present in the index patient's lung fluid and groin. Since patients 1 and 4 did not overlap in the hospital, this case suggested that there may have been an undetected patient who was asymptomatically colonized and acted as a transmission intermediary. Such detailed understanding of how infections spread in the hospital was previously unattainable.

Most K. pneumoniae present in U.S. hospitals are closely related. Because of this, most current infection surveillance techniques are unable to provide the degree of resolution necessary to identify even the big-picture relationships of K. pneumoniae strains among hospitals, much less the fine-scale relationships of strains within a hospital. But because whole genome sequencing is able to pinpoint any genomic variation that exists between bacteria, it is able to provide the resolution necessary for tracing within-hospital spread of infections.

In addition, the scientists identified key insights into the evolution of drug resistance. The K. pneumoniae introduced by the first patient was resistant to many antibiotics. What's more, throughout the course of the outbreak, some bacterial isolates were observed to have become resistant to all currently known antibiotics, leaving no effective treatment options for some patients. Resistance to polymixin E, an antibiotic of last resort, appeared to have evolved independently in all three patient clusters. In two different cases, the mutations conferring polymixin E resistance were found to alter proteins associated with membrane function, possibly allowing the bacteria to prevent or decrease the amount of drug entering the cell. This finding demonstrates the potential of genomic sequencing to shed light on the evolution of resistance and on more effective tailoring of therapeutic regimens.

Hospital-acquired infections have become an increasingly urgent issue due to the rising incidence of antibiotic resistance. The rapidly declining cost and increasing speed of genome sequencing may help clinical epidemiologists bolster their tool kit. In real time, whole bacterial genome sequencing will allow investigation with unprecedented resolution of how infections spread. According to Dr. Snitkin, "With highly resistant pathogens such as Klebsiella, where treatment options are quickly dwindling, the application of new technologies to understand how best to prevent infections, is essential." This study demonstrates how genomic sequencing can lead to actionable insights that inform hospital practice.

Study reference: Tracking a Hospital Outbreak of Carbapenem-Resistant Klebsiella pneumoniae with Whole-Genome Sequencing. Science Translational Medicine, Aug. 22, 2012. [PubMed]

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Posted: October 2, 2012