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Antimicrobial Agents and Chemotherapy, October 2005, p. 4144-4148, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4144-4148.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Relationship between the Level of Acquired Resistance to Gentamicin and Synergism with Amoxicillin in Enterococcus faecalis

Elisabeth Aslangul,¹ Raymond Ruimy,^1* Françoise Chau,¹ Louis Garry,² Antoine Andremont,¹ and Bruno Fantin¹

EA9933, Faculté de Médecine Xavier Bichat, Université Paris 7, 16 rue Henri Huchard, BP416, 75870 Paris Cedex 18,¹ INSERM U722, Faculté de Médecine Xavier Bichat, Université Paris 7, 16 rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France²

Received 24 February 2005/ Returned for modification 16 May 2005/ Accepted 17 July 2005

In enterococci, intrinsic low-level resistance to gentamicin does not abolish synergism with a cell wall-active antibiotic while high-level resistance due to acquired aminoglycoside-modifying enzymes does. To study the impact of intermediate levels of resistance to gentamicin (64 < MIC < 500 µg/ml), we selected in vitro three consecutive generations of mutants of Enterococcus faecalis JH2-2 with MICs of gentamicin at 128 µg/ml for G1-1477, 256 µg/ml for G2-1573, and 512 µg/ml for G3-1688. E. faecalis 102, which is highly resistant to gentamicin by enzymatic inactivation was used as control. In in vitro killing curves experiments, gentamicin concentrations allowing bactericidal activity and synergism in combination with amoxicillin increased from 4 µg/ml (1/16th the MIC), 16 µg/ml (one-eighth the MIC), 64 µg/ml (one-quarter the MIC), and 256 µg/ml (one-half the MIC) for strains JH2-2, G1-1477, G2-1573 and G3-1688, respectively. As expected, no bactericidal effect of the combination or synergism could be obtained with strain 102. In rabbits with aortic endocarditis caused by strain G1-1477 or G2-1573, combination therapy with amoxicillin and gentamicin was significantly more active than amoxicillin alone (P < 0.05) but not in those infected with the strains G3-1688 and 102. Thus, intermediate levels of resistance to gentamicin was not associated with a loss of a beneficial effect of the gentamicin-amoxicillin combination in vivo even though higher concentrations of gentamicin were necessary to achieve in vitro synergism. Therefore, the use of an MIC of 500 µg/ml as a clinical cutoff limit to predict in vivo benefit of the combination remains a simple and effective tool.

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* Corresponding author. Mailing address: Hôpital Bichat-Claude-Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. Phone: 33140258505. Fax: 33140258505. E-mail: raymond.ruimy{at}bch.aphp.fr.

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Antimicrobial Agents and Chemotherapy, October 2005, p. 4144-4148, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4144-4148.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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