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Novel Approach Slows C. Difficile Growth In Mice

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  • Novel Approach Slows C. Difficile Growth In Mice

    <table bgcolor="white" border="0" cellpadding="0" cellspacing="0"><tbody><tr><td width="8">
    </td> <td colspan="3" class="large_head2" valign="top">ICAAC: Novel Approach Slows C. Difficile Growth In Mice

    </td></tr></tbody></table>By Michael Smith, Senior Staff Writer, MedPage Today
    Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
    September 18, 2007


    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.
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    Action Points
    • Explain to interested patients that Clostridium difficile disease, which can be life-threatening, is caused by the effects of antibiotics on the microflora of the gut.
    • Explain that this early study suggests that -- for some drugs -- it may be possible to prevent the disease by using an enzyme that blocks the activity of the medications in the gut while leaving them active in the rest of the system.
    • Note that this study was published as an abstract and presented orally at a conference. The data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

    <o:p></o:p> 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.

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    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.<o:p></o:p>
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    In murine trials and some European phase I trials, this approach appeared both safe and effective, she said.

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    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.

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

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    Dr. Stiefel and colleagues tested the enzyme in mice and found that it almost completely prevented antibiotic-associated overgrowth of C. difficile.<o:p></o:p>
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    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.

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    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.

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    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.

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    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.<o:p></o:p>
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    On the other hand, C. difficile growth in cultures from the animals treated with the antibiotics alone was significantly greater (at P<0.0001) and was not different from that seen in cultures from animals given the drugs, enzyme, and tazobactam.

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    Dr. Stiefel said that such a procedure might be used in patients for whom there was no substitute for beta-lactam antibiotics, although she said it will take five or 10 years of study before the approach could be used in humans.

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    She noted that if the idea works it might be applicable -- through different mechanisms -- to prevent the adverse effects of other classes of antibiotics.

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    The study provided "interesting data," but has a long way to go before it's ready for prime time, according to session chairman Mark Wilcox, M.D., of Leeds University in England, who was not involved in the research.

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    In an interview after the presentation, Dr. Wilcox noted that the idea would only be useful if the sole antibiotic therapy for a patient consisted of beta-lactam drugs.

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

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    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.

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


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    <table bgcolor="#a0d7f6" border="1" cellspacing="0" hspace="1"> <tbody><tr><td>Several of the co-authors of the abstract are employees of Ipsat Therapies Ltd., the developer of the enzyme used in the study.<o:p></o:p> </td></tr></tbody></table>


    Complete ICAAC Coverage

    Primary source: Interscience Conference on Anti-microbial Agents and Chemotherapy.<o:p></o:p>
    Source reference:
    U. STIEFEL et al "Orally Administered ?-Lactamase Enzymes Represent a Novel Strategy to Prevent Colonization by Clostridium difficile" Presentation number K-607.
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