CHARLESTON, SC—There are two major challenges facing the medical community when it comes to tackling MRSA and other hospital-related infections: finding new and innovative ways to stop the spread of the organisms within hospitals, and discovering how these organisms operate internally. The first challenge has a wealth of clinical data—much of it gathered at the Department of Veterans Affairs—to guide it. The second challenge, that of dissecting these organisms genetically and otherwise to see how they work, is an effort still in its infancy.

According to Dr Joseph John, an infectious disease expert at the Ralph Johnson VA Medical Center in Charleston, SC, it was only with the beginning of the 21st century that the medical community realized that hospital infections, especially the increase of antibiotic-resistant organisms like MRSA, presented a problem that needed to be immediately addressed.

“Throughout the 1970’s, 80’s and 90’s, we used to estimate a rate of about 5% of everybody who went into hospitals would acquire a hospital-associated infection. Now, that might seem to be unacceptably high, but that was the data,” Dr John explained. “As we came into this century, there was a new realization that we had to do something about the 5% of people and the billions of dollars it was costing us to face hospital infections. Ironically, at the same time, we were having large upswings in infections due to [MRSA].”

As hospitals began to refocus attention on how these organisms spread, it was discovered that the bulk of infections were in intensive care units and most often had to do with ventilator-dependent patients and patients with central venous catheters. “Real attention to hand washing and what we would call check-lists, particularly in our intensive care units, had not been really operative until work was published in the New England Journal of Medicine 2 to 3 years ago,” Dr John said. “That work showed that if we all take a much more assembly-line view—a view that some physicians and nurses don’t like to think of because it suggests the automation of our activity—we can minimize the kinds of breaks in techniques that account for some of the exposure for bacterial and fungal infections in hospitals.” However, recognizing how such organisms are spread is a piece of what is needed to slow their spread.

Metallurgy in Combating Infection

Over the last few years, VA has rolled out an intensive infection prevention campaign focusing particularly on MRSA, with its foundation being the documentation and tracking of all MRSA-infected patients coming into and leaving VA hospitals. The second major part of the initiative is making every VA employee that has contact with a patient or contact with equipment a patient might touch very hygiene conscious. By cutting down on the amount of organisms found in a hospital room, VA hopes to cut down on the number of infections in its patients.

Dr John and fellow researchers are concerned with making it harder for such organisms to find purchase on hospital surfaces in the first place. “We are focused on the effects of altering the environments in high-risk areas such as intensive care units,” he said. “One of the approaches we’ve hit on in cooperation with metal experts in places like the Copper Development Association, is that copper, along with only silver, are the only antibacterial metals that we have.”

The majority of hard surfaces in a hospital room are made of metals like steel, iron, lead, or tin, or plastics, none of which are antibacterial, and they get contaminated easily. “We’re in the process of placing copper on to touch surfaces in intensive care units. This would provide the potential of decreasing the Staphylococcal and other infection burden within these intensive care units,” Dr John explained. “It is our hope that by reducing that burden [it will lower the risk] of patients in those rooms acquiring a hospital-acquired infection.”

Whether that correlation is true or not will be examined in Phase 3 of the trial. Currently Dr John is examining whether putting copper in the room will indeed reduce surface contamination. The study, being funded by the Department of Defense, should produce data related to patient infection by the end of 2010, Dr. John said.

The Research Burden

The Gordon Research Conference on Staphylococcal diseases—presenting the most cutting edge research into Staph aureus—was held last month in New Hampshire. While data presented at the conference is confidential, Dr John said that there are certain areas in the field of hospital infection where research attention is, and needs to be, focused.

These include evolution of the Staphylococcus organism, which is adding and subtracting genes constantly and making itself a more complicated organism, Dr John said. Also, antibiotic resistance in Staph aureus has been expanding and becoming more complicated—a phenomenon that needs to be better documented and understood. “In terms of vaccine development, what we would call innate immunity—the way our bodies would naturally respond to any outside microbial threat—that immunity has also not been well described,” Dr John explained. “[Researchers] have been working hard to try and understand why it is these organisms can gain access to vital sites in our body without much obstruction from our natural immunity.”

Researchers also need to better understand how the bacterium regulates itself in terms of its genetic make-up. “What turns on and off individual genes? How does it make protein? And more importantly, for the many toxins that staph aureus has—let’s say 10 to 12 toxins—how are those toxins mediated and what turns them on and off?” Dr John asked.

One growing problem is the ability of many of these organisms to create biofilm—a complex combination of nucleic acids, proteins, and sugars that provide protection and render the microorganism less susceptible to antibiotics. “When they get comfortable, want to set up shop, want to settle down for a while, they’ll start to think of where they are as home, and put down biofilm and make themselves more comfortable in that sanctuary,” Dr John explained. “We don’t have any way right now to turn off the biofilm or prevent it. There are probably 20 genes in Staph aureus that can contribute to biofilm production. So it is a tremendous challenge in this era. Some experts estimate that up to 65% of all infections may have some relationship to their ability to make biofilm.”

But the challenge that has proven the most difficult—the Holy Grail of this field of research—is the discovery of viable animal models for Staph infection. Staph aureus is a somewhat species-specific infection, affecting different animals in different ways. “Cats have their own type of Staph aureus, as do dogs and horses. Cows have a terrific problem with bovine mastitis due to Staph aureus,” Dr John said. “The kinds of infections that humans get with Staph aureus are hard to produce in animals, though not impossible.”

For years, researchers have worked with small worms called C elegans, and recently work has been done on zebrafish that can be manipulated for Staph infections. But ultimately, Dr John noted, vaccine immune strategies and new antimicrobials must be tested on humans.

The Goal of a Vaccine

All of these issues—from genomics to proteomics, metabolomics, and innate immunity—raise the question of will we ever free ourselves from bacterial infection with vaccines, Dr John stated. “Merck [Pharmaceuticals] is working hard on a vaccine, as are a few other companies, and we’re standing by,” he said. “The Merck trial has enrolled about 3,000 patients, and it’s heading toward 10,000. It’s a massive study, and even if it’s not successful in reducing Staphylococcal infections, it will give us a wonderful basis for the performance of these types of large-scale Staph vaccine trials.”

And it is an effort that might very well require some trial and error. “I think our culture and our civilization has been spoiled by certain vaccines, including influenza vaccines, which are quite good,” Dr John said. “And we have to realize we have not been very successful in making bacterial vaccines to protect us against bacterial infections. So patience is required.”

In the meantime, Dr John’s desire is to better understand how these organisms work and how they spread, so that he can help patients understand it themselves. “It’s hard to convey to patients the fact that we are protected by these organisms—30% of us house Staph aureus and almost 100% of us carry Staphylococci, known as coagulase negative Staphylococci. And depending on our own host situation, those organisms can become germs that infect us. That’s a very difficult concept. It’s difficult for us scientists, as well as very difficult patients to understand,” Dr John declared. “What I’m trying to paint is a picture of us getting at a level of understanding that is deep and is very scientific, but we’re a long way from knowing all the subtleties and the mechanism by which not only Staph aureus, but other Staphylococci and other organisms living on and in us cause infection.”

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