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Tracking the Spread of Bacteria Around the Globe with DNA Sequencing

Worldwide Pandemics of Antibiotic Resistant Bacteria

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Tracking the Spread of Bacteria Around the Globe with DNA Sequencing

Human Neutrophil Ingesting MRSA

National Institute of Allergy and Infectious Diseases (NIAID)

In addition to enabling much more precise and informative tracking of local outbreaks of infectious disease, as outlined in Genetic Analysis Improves Medicine's Response to Infections Outbreaks, advanced high-throughput DNA sequencing technology now also enables scientists to track the spread of bacterial pandemics around the globe. A couple of just published studies took advantage of this approach to look at the spread of two particularly aggressive antibiotic-resistant infectious bacteria. By analyzing the differences in the bacterial DNA of samples collected from patients around the world, the researchers determined how closely related the bacteria from different patients were, and so, were able to track the spread of strains across the globe.

The groups mapped the spread of two pathogens that are particularly nasty and resilient. Both are antibiotic resistant strains that have appeared in the last couple decades and often infect hospitalized patients. Once established, they are particularly difficult to eliminate. One group looked at the colonization of highly resilient strains of diarrhea-causing Clostridium difficile from the US to Europe and Asia, and the other, the spread of the “flesh-eating bacteria” methicillin-resistant Staphylococcus aureus (MRSA).

C. difficile Colonizes Europe from North to South

About a decade ago, a particularly virulent strain of C. difficile started cropping up in North America. This bacteria infection usually flairs up in hospitalized patients on antibiotics since the antibiotics kill off competing bacterial in the individual, which gives the resistant C. difficile an opportunity to flourish. Infections can be very serious, difficult to cure, last extended periods, and are sometimes even be fatal.

Around 2004, outbreaks of resistant C. difficile began occurring in hospital in England, then a bit later in Europe and most recently Australia. Almost half of the C. difficile infections in the United Kingdom are the resistant strain that first cropped up in North America.

How did this antibiotic resistant strain of C. difficile spread so far so fast? In an attempt to answer this, a consortium of international researchers from 23 laboratories used high-through DNA sequencing to analyze the whole C. difficile genome of 151 infected patients around the world.

Two Main Types of Antibiotic Resistant C. diff

One of the first things the researchers noticed was that there were actually two different variants of antibiotic-resistant C. difficile. In other words, mutations of normal bacteria to produce the antibiotic resistant lines happened at least two distinct times, and each spread independently. Though the mutations that each of the strains contains are different, both sets result in the same antibiotic resistance. They are specifically resistant to fluoroquinolone antibiotics and indicate the key genetic changes needed to enable the bacteria to tolerate these chemicals.

Both resistant lineages also originated in the US around the same time. One appeared first in Pennsylvania in 2001, which is where the earliest reported of outbreaks of resistant C. difficile in hospitals occur. This strain, however, only appeareds to have migrated to S. Korea and Switzerland.

The other resistant C. difficile strain surfaced a year or so later with an outbreak in Montreal, though it probably originated south of the Canadian border in the US. This is the lineage that accounts for most the worldwide cases of resistant C. difficile infection. It spread from the North-East US or Eastern Canada to the UK, other parts of Europe, and eventually Australia. It was introduced at least three different times into England and twice into continental Europe. Then, of course, there was cross infection between the United Kingdom and Europe.

MRSA Makes Its Way Out of the UK

The second study, also undertaken by a consortium of labs from around the world, tracks the global spread of methicillin-resistant Staphylococcus aureus, better known by its acronym MRSA, or sometimes more ominously called flesh-eating bacteria. Methicillin, a variation of pencillin, was a common treatment for range of Staphylococcus infections since the 1950s.

Antibiotic resistant MRSA was first detected several decades ago, but the researchers focused on a particularly aggressive and “tenacious,” as they described it, strain that was detected in the 1990s in the UK, then spread throughout Europe and the world. This strain, often referred to as Epidemic MRSA, accounts for the majority of hospital infections in Europe. The investigators looked at 193 cases of infection with a specific Epidemic MRSA strain from all across the globe.

It appears that the particularly aggressive line of Epidemic MRSA emerged in the British Midlands in the early 1990s and infected most of the UK over the following decade. The strain was also repeatedly introduced to Germany, Denmark, and Austria during this time and, from there, spread out and infected most of Europe, northern Africa, and Australia. Suprisingly, this strain is still relatively rare in the Americas and large parts of Asia.

Fluorquinolone Antibiotic Resistance and Hospital Colonization

While the MRSA study provided a wealth of information about the specific genetic characteristics of the aggressive epidemic strain, it wasn’t able to definitely answer why that strain was so successful at colonizing most of the world’s hospitals. It did, however, offer some clues, and one, in particular, overlaps with the C. difficile study mentioned above. Both studies note that the appearance of these resistant bacteria strains coincide with the introduction and widespread use of fluorquinolone antibiotics in the 1990s.

The authors of the C. difficile note that fluoroquinolone antibiotics were one of the most commonly prescribed antibiotics in North America during the late 1990s so the “near-simultaneous emergence” of more than one lineage of resistant C. difficile strain is probably a result of the strong selective pressure for resistant during this period. Also, it turns out that the aggressive Epidemic MRSA strain is also resistant to fluoroquinolone, despite the fact that Staphylococcus infections aren’t usually treated with these type of antibiotics.

When an individual’s normal bacteria are decimated by treatment with fluoroquinolone antibiotics, a common occurrence in hospitals, both of these resistant pathogens can take advantage of the opportunity. In fact, the authors of the MRSA study point to a specific study showing that MRSA infections increase following widespread fluoroquinolone use. It seems both of these bacteria have migrated around the world colonizing an ecological niche hostile to other microbes—namely, hospitals and patients filled with antibiotics. It’s both an interesting and concerning adaptation. Let's hope these two strains, and a few other similar cases, aren't the first colonists of a full-scale invasion.

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