ICAAC: Novel Approach Slows C. Difficile Growth In Mice

September 18, 2007

CHICAGO -- A pre-emptive strike against antibiotics like penicillin, which are frequently implicated in Clostridium difficile disease, may prevent this life-threatening condition, a Cleveland researcher said here.

CHICAGO, Sept. 18 -- A pre-emptive strike against antibiotics like penicillin, which are frequently implicated in Clostridium difficile, disease may prevent this life-threatening condition, a Cleveland researcher said here.

The beta-lactams, which are widely used, top the list of usual suspects in

C. difficile disease, according to Usha Stiefel, M.D., of the Veterans Administration Medical Center in Cleveland.

But treating patients with an enzyme that inactivates the drugs in the intestines - before they are given beta-lactam antibiotics -- is a "novel approach" that might prevent disease, Dr. Stiefel told attendees at the Interscience Conference on Anti-microbial Agents and Chemotherapy.

In murine trials and some European phase I trials, this approach appeared both safe and effective, she said.

The enzyme, a recombinant version of beta-lactamase that resists degradation in the intestines, blocked the activity of the antibiotics in that region, which prevented the overgrowth of C. difficile that leads to disease, she said.

Dr. Stiefel noted that studies in dogs have shown that the enzyme remains in the intestinal lumen and has little or no systemic activity.

Dr. Stiefel and colleagues tested the enzyme in mice and found that it almost completely prevented antibiotic-associated overgrowth of C. diffile.

The animals were treated subcutaneously with one of two beta-lactam antibiotics - ampicillin (Principen) or piperacillin (Pipracil) - at doses comparable to human therapeutic levels, she said.

Some of the mice also were given the beta-lactamase enzyme orally. A third group was given the antibiotic, the enzyme, and tazobactam, which blocks the activity of beta-lactamase. Control mice were given normal saline.

After 24 hours the mice were sacrificed and their intestinal contents were inoculated with one of four strains of C. difficile and cultured for another 24 hours.

At the end of that time, the growth of C. difficile in cultures from the animals given saline was "not significantly different" from what was seen in cultures from the mice given antibiotics plus the enzyme, Dr. Stiefel said.

On the other hand, C. difficile growth in cultures from the animals treated with the antibiotics alone was significantly greater (at P

If, as if often the case, patients were on "polypharmacy," the enzyme treatment would have no effect, he said.

Dr. Wilcox added that the study showed only that the enzyme prevented overgrowth of C. difficile, but didn't have provide information on what toxins might have been produced by bacteria that did grow.

"It's the toxins we are really concerned with," he said.

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