New treatment shows promise

A new, double-barrelled approach to treating C. difficile appears to dramatically reduce recurrence of the debilitating and potentially deadly infection, preliminary testing suggests.

TORONTO — A new, double-barrelled approach to treating C. difficile appears to dramatically reduce recurrence of the debilitating and potentially deadly infection, preliminary testing suggests.

Researchers developed two drugs, called monoclonal antibodies, which are aimed at neutralizing two toxins produced by Clostridium difficile, a common bacterium that can infect the gastrointestinal tract and cause severe diarrhea in vulnerable patients.

A small study found that injections of the monoclonal antibodies along with specific antibiotics used to treat C. difficile reduced the recurrence of the disease by 72 per cent.

“We’re really hopeful that this is a new therapy and a new option for patients,” said Dr. Donna Ambrosino of the University of Massachusetts Medical School, which co-developed the drugs.

“Larger studies will have to be done before it can be licensed and available to patients,” Ambrosino said from Boston. “But we’re quite confident, given these results, that with larger studies that will be shown, and ultimately that this would be a therapy that would prevent those recurrences.”

The study compared 200 patients with C. difficile in 30 centres across the United States and Canada, from July 2006 through April of 2008.

Half were randomly assigned to receive antibiotics plus a single injection of the monoclonal antibodies, while the other half were treated with antibiotics and a shot containing a placebo. Patients were then monitored for almost three months.

The research, published in this week’s New England Journal of Medicine, is what’s called a Phase 2 study, conducted to determine safety of the drugs and optimal dosing. But in analyzing their data, the researchers found a significant difference in how the two groups fared.

Results showed only seven per cent of patients who received the antibodies suffered a recurrence, compared to 25 per cent of those in the placebo group — a 72 per cent difference in the relapse rate.

Of 44 patients infected with the epidemic strain of C. difficile, NAP-1, only eight per cent of those given the antibodies suffered a relapse, versus 32 per cent of those given a dummy shot.

The monoclonal antibodies were developed by the University of Massachusetts’ non-profit MassBiologics arm and Medarex, a subsidiary of Bristol-Myers Squibb. Rights have been licensed to Merck, which would be responsible for undertaking larger studies to confirm the drugs’ effectiveness before seeking government approval to market them.

“I think the statistics are impressive,” said Dr. Dale Gerding, an infectious disease specialist at Loyola University, where lab work on the C. difficile organisms was performed for the study.

“This is a quite effective strategy, it appears,” Gerding said from Chicago. “Getting recurrence rates down to single digits (seven per cent) when your placebo group is running at 25 per cent is really quite significant.”

C. difficile is widespread in the environment, with up to five per cent of the population carrying it without ill effect. But for some patients, taking certain antibiotics or other drugs can disrupt natural flora in the intestinal tract, allowing the bacterium to proliferate.

That can lead to severe diarrhea, bowel disease or potentially fatal blood poisoning.

A virulent epidemic strain, known as NAP-1, killed an estimated 2,000 patients in Quebec in the last 10 years, and other outbreaks of the bug caused scores of deaths in some Ontario hospitals.

C. difficile produces spores that can contaminate surfaces and are difficult to eradicate, making it one of the most common causes of infectious diarrhea in hospitals and long-term care homes.

“What happens, we think, in almost every case is you take the antibiotic, your flora is disrupted and then you also have to ingest or pick up the organism,” said Gerding.

“Then if you lack antibody (against C. difficile), as many elderly people do, then you become symptomatic.”

“We know that if you stay in the hospital after you’ve been treated that your rate of recurrence is higher … presumably that’s because you’re exposed to the organisms more because of the contaminated environments in hospitals.”

“The really distressing part of it is what you went there for, you got taken care of. But now you’ve got this new thing that doesn’t want to go away. And it does extremely debilitate people, especially if they’re older. And it just upsets their recuperation from the other problems and it puts them on medication for months and months and months.”

Gerding said the monoclonal antibody is intended to boost the immune system’s ability to fight off the infection, allowing patients to recover faster.

“The trial results are impressive,” Dr. Lorraine Kyne, a geriatric medicine specialist at University College Dublin, wrote in an accompanying editorial. “This novel non-antibiotic approach to secondary prevention is likely to offer hope to physicians and patients battling C. difficile infection.”

Ambrosino, executive director of MassBiologics and a professor of pediatrics at the University of Massachusetts, said a number of monoclonal antibodies have been developed over the last decade as treatments for certain cancers, rheumatoid arthritis and multiple sclerosis.

Those aimed at C. difficile represent only the second time the drug type has been used successfully against an infectious disease (the other is respiratory syncytial virus in infants), she said, adding that her team is studying other monoclonal antibodies for rabies and hepatitis C.

“I think there’s room for many more infectious diseases to be attacked by monoclonal antibodies, and we’re quite hopeful.”