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The hardy superbug C. difficile infects hundreds of thousands of North American hospital patients per year — in rare cases, it proves fatal. NRC is developing non-antibiotic therapies, which target molecules that give the bacteria its virulence.
An 80-year-old woman is admitted to hospital with pneumonia. Her doctor prescribes life-saving antibiotics, but as her lungs start to clear, she develops gastrointestinal problems including diarrhea, loss of appetite, nausea and abdominal pain. It turns out the very antibiotic used to cure her pneumonia has also destroyed good bacteria in her gut — allowing an opportunistic pathogen called Clostridium difficile (C. difficile) to multiply.
C. difficile — a so-called “superbug” because of the frequency of cases, its persistence in hospitals and its resistance to treatment — naturally resides in a small percentage (up to 15 percent) of the population, but is kept in check by normal intestinal bacteria. “In hospitals, intravenous antibiotics promote the proliferation of C. difficile,” says Dr. Françoise Giard, a dermatologist who heads the Infection Control Committee at the Gatineau Hospital in Quebec. “This means a certain number of C. difficile infections are inevitable because some patients must be treated with antibiotics, otherwise they will die.”
In hospitals, intravenous antibiotics promote the proliferation of C. difficile.
The good news is that most people diagnosed with C. difficile get better (see how hospitals are coping with C. difficile infections). But infections can have serious complications, including colitis — in rare cases, colectomies are required and the infection can prove fatal.
“We’ve treated C. difficile infections in the past, but the number of cases has really increased over the last decade,” says Dr. Giard. In around 2000, a new, highly virulent strain of the bacteria emerged in North America and has since been found in Europe and Australia. According to Statistics Canada, more than 1,000 Canadians died in hospitals of C. difficile infections in 2007.
Current treatments have drawbacks
For serious cases, doctors usually prescribe an antibiotic powerful enough to kill the bacteria, such as vancomycin. However, while certain antibiotics may clear a person’s body of C. difficile, they won’t clear out the bacteria’s spores, which are resistant to drugs. “When the treatment stops, if you haven’t recolonized your gut with good bacteria, C. difficile spores will germinate and start producing toxin again,” says Dr. Susan Logan of the National Research Council (NRC). “Patients may go home, but two weeks later they may be back in the hospital with a recurrent infection and have to undergo antibiotic treatment again.” She adds that if such patients have serious complications, the treatment of last resort is a fecal transplant from a sibling donor, which is used to re-colonize their digestive tract with “good” harmless bacteria that prevent C. difficile infection.
An expensive superbug
C. difficile is the most common cause of infectious diarrhea in hospital patients in the industrialized world. Across North America, the organism infects hundreds of thousands of people per year — seniors and patients with weakened immune systems are the most at risk. According to various studies, the estimated health-care cost in the U.S. alone is up to $3 billion per year.
“Another concern is the emergence of antibiotic-resistant superbug strains that cannot be treated using existing antibiotics,” says Dr. Jamshid Tanha, also of NRC.
To address these challenges, the two NRC researchers are developing different strategies for treating C. difficile, which involve targeting specific molecules that give the bacteria its virulence — as opposed to killing the actual bacteria.
Strategy 1: Disarming the toxins that cause illness
Coping with C. difficile
Hospitals across Canada deal with C. difficile infections through the careful (optimal) use of antibiotics, by isolating patients to prevent the bacteria from spreading, and by treating them with more powerful antibiotics, if necessary. (More)
Dr. Tanha’s approach involves a family of antibodies — first discovered in llamas and camels — that have a “single-domain” for recognizing molecules and are 10 times smaller than the antibodies found in humans. Dr. Tanha and his colleague Greg Hussack have developed single-domain antibodies that recognize two C. difficile toxins that cause the symptoms associated with an infection.
The researchers envision giving patients antibodies in the form of pills — this would be like swallowing tiny pieces of Velcro that stick to and trap the toxins, which would ultimately allow the repopulation of healthy bacteria. Dr. Tanha says that oral therapeutics would likely be easier and less expensive to administer than antibody injections.
The main challenge in developing orally administered antibodies is to engineer them to survive the digestive tract. “We need to make sure they’re resistant to digestive enzymes, as well as the acid environment of the stomach,” says Dr. Tanha. “Otherwise, they may degrade and fail to function properly.” The team has shown that several of its antitoxin antibodies are resistant to both acidity and gastrointestinal digestive enzymes.
Strategy 2: Preventing bacteria from swimming
Elsewhere at NRC, Dr. Susan Logan and her colleague, Dr. Robert Ménard, are searching for ways to prevent C. difficile from growing a flagellum, a protein tail that allows the bacteria to “swim” and colonize the colon. “Instead of trying to kill the bacteria, we’re trying to manage the disease by disabling the ability of the bacteria to move toward and colonize the colon,” says Dr. Ménard.
C. difficile’s flagellum contains a specific carbohydrate (sugar) molecule. Working with similar organisms (see box), Dr. Logan discovered that the flagellum sugars are key to the assembly of the bacteria’s tail and its subsequent colonization of the gastrointestinal tract. “If we can knock out the ability of C. difficile to make its carbohydrate, it can’t form flagella,” she says. So far, the team has identified enzymes in the pathway that synthesizes this carbohydrate, and is now searching for molecules that can stop these enzymes from working properly. (Complementing this work, Dr. Tanha’s team has developed antibodies that can bind to surface proteins found on C. difficile, which would disable its attachment to the colon.)
Research origins
Dr. Susan Logan’s research on C. difficile grew out of previous research on Helicobacter pylori, a stomach pathogen that causes gastric ulcers. “We discovered that we can target the sugar biosynthetic pathway involved in forming flagella in H. pylori,” says Dr. Logan. “Using a small molecule inhibitor identified in Dr. Ménard’s lab, we can prevent the sugar from being produced, which should prevent the organism from propelling itself. If H. pylori bacteria cannot swim, they will get washed out of the digestive system and hence can no longer cause disease.”
A combination of therapies
Both NRC teams believe that their approaches, if approved for clinical use, have the potential to work well together, or in combination with antibiotics. “The anti-toxin antibody therapy would minimize the virulence of C. difficile, while our approach would help clear the organism,” says Dr. Ménard. “Targeting more than one virulence factor unique to C. difficile is probably the most logical approach for ensuring that a patient’s infection doesn’t recur,” adds Dr. Logan. 
