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Orally Administered Targeted Recombinant Beta-Lactamase Prevents Ampicillin-Induced Selective Pressure on the Gut Microbiota: a Novel Approach to Reducing Antimicrobial Resistance

Jaana Harmoinen,^1* Silja Mentula,² Matti Heikkilä,¹ Michel van der Rest,³ Päivi J. Rajala-Schultz,⁴ Curtis J. Donskey,⁵ Rafael Frias,¹ Pertti Koski,⁶ Nina Wickstrand,⁶ Hannele Jousimies-Somer,^2, Elias Westermarck,¹ and Kai Lindevall⁷

Faculty of Veterinary Medicine, Department of Clinical Veterinary Sciences, 00014-University of Helsinki, Helsinki,¹ Anaerobe Reference Laboratory, Department of Microbiology, National Public Health Institute (KTL), 00300 Helsinki,² Ipsat Therapies Ltd., 00710 Helsinki,⁶ Remedium Clinical Research/Ipsat Therapies Ltd., 02630 Espoo, Finland,⁷ Microscreen BV, 9713 GX Groningen, The Netherlands,³ College of Veterinary Medicine, Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, Ohio 43210,⁴ Infectious Diseases Section, Louis Stokes Cleveland Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, Ohio 44106⁵

Received 11 March 2003/ Returned for modification 6 September 2003/ Accepted 6 October 2003

Antibiotics that are excreted into the intestinal tract promote antibiotic resistance by exerting selective pressure on the gut microbiota. Using a beagle dog model, we show that an orally administered targeted recombinant ß-lactamase enzyme eliminates the portion of parenteral ampicillin that is excreted into the small intestine, preventing ampicillin-induced changes to the fecal microbiota without affecting ampicillin levels in serum. In dogs receiving ampicillin, significant disruption of the fecal microbiota and the emergence of ampicillin-resistant Escherichia coli and TEM genes were observed, whereas in dogs treated with ampicillin in combination with an oral ß-lactamase, these did not occur. These results suggest a new strategy for reducing antimicrobial resistance in humans.

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