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Antimicrobial Agents and Chemotherapy, June 2009, p. 2455-2462, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00853-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

P1A Recombinant β-Lactamase Prevents Emergence of Antimicrobial Resistance in Gut Microflora of Healthy Subjects during Intravenous Administration of Ampicillin{triangledown}

Ann-Mari Tarkkanen,1 Tuula Heinonen,1,{dagger} Rain Jõgi,2 Silja Mentula,3 Michel E. van der Rest,4 Curtis J. Donskey,5 Tuomas Kemppainen,6 Konstantin Gurbanov,1* and Carl Erik Nord7

Ipsat Therapies Oy/Ltd., FIN-00790 Helsinki, Finland,1 Tartu University Hospital, Lung Clinic, Tartu, Estonia,2 Anaerobe Reference Laboratory, Department of Bacterial and Inflammatory Diseases, National Public Health Institute (KTL), FIN-00300 Helsinki, Finland,3 BioVisible, L. J. Zielstraweg 1, 9713 GX Groningen, The Netherlands,4 Infectious Diseases Section, Louis Stokes Cleveland Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, Ohio 44106,5 4 Pharma Ltd., Lemminkaisenkatu 1, FIN-20520 Turku, Finland,6 Department of Laboratory Medicine, Division of Clinical Bacteriology, F 83, Karolinska University Hospital Huddinge, Karolinska Institute SE-14186 Stockholm, Sweden7

Received 27 June 2008/ Returned for modification 31 August 2008/ Accepted 8 March 2009

Ipsat P1A is a recombinant β-lactamase which degrades antibiotic residue in the gastrointestinal tract. In an open-label, single-center controlled trial, 36 healthy subjects were randomized to receive (i) ampicillin (1 g intravenously [i.v.] every 6 h [q6h]), (ii) oral P1A recombinant β-lactamase (8.2 mg q6h), or (iii) ampicillin (1 g i.v. q6h) in combination with oral P1A recombinant β-lactamase (8.2 mg q6h) for 5 days. Fecal samples were collected before treatment, during treatment (days 3 to 5), and at follow-up (day 12). The primary end points were (i) changes in gastrointestinal microflora (determined by temperature gradient gel electrophoresis [TGGE]) and (ii) emergence of bacterial resistance (determined by conventional microbiology and PCR of TEM β-lactamase genes). Thirty-five subjects completed the study. The mean similarity percentages of TGGE profiles between baseline and each treatment day sample were significantly lower for the ampicillin group than for the group receiving ampicillin plus P1A recombinant β-lactamase on days 3, 4, and 5 (P < 0.001). Compared with the ampicillin group, subjects receiving ampicillin plus P1A recombinant β-lactamase had significantly fewer ampicillin-resistant coliforms on days 3, 4, and 5 and at follow-up (P ≤ 0.001) and fewer TEM β-lactamase genes on days 3, 4, and 5 (P < 0.02). P1A recombinant β-lactamase was safe and well tolerated. In healthy subjects, P1A recombinant β-lactamase prevents ampicillin-induced alterations in intestinal microflora, emergence of resistance, and the number of TEM genes.

* Corresponding author. Mailing address: Ipsat Therapies, Viikinkaari 4, FI-00790 Helsinki, Finland. Phone: 358 9 31936507. Fax: 358 9 31936519. E-mail: konstantin.gurbanov{at}ipsat-ther.com

{triangledown} Published ahead of print on 23 March 2009.

{dagger} Present address: Medical School, University of Tampere, FI-33014 Tampere, Finland.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2455-2462, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00853-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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