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Antimicrobial Agents and Chemotherapy, March 1999, p. 639-646, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Efficacy of Ampicillin plus Ceftriaxone in Treatment of Experimental Endocarditis Due to Enterococcus faecalis Strains Highly Resistant to Aminoglycosides

Joan Gavaldà,1,* Carmen Torres,2 Carmen Tenorio,2 Pedro López,1 Myriam Zaragoza,2 Josep A. Capdevila,1 Benito Almirante,1 Fernanda Ruiz,2 Nuria Borrell,1 Xavier Gomis,1 Carles Pigrau,1 Fernando Baquero,3 and Albert Pahissa1

Infectious Diseases Research Laboratory, Infectious Diseases Division, Hospital General Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona,1 Universidad de la Rioja, Logroño,2 and Microbiology Service, Hospital Ramón y Cajal, Madrid,3 Spain

Received 17 February 1998/Returned for modification 27 April 1998/Accepted 30 December 1998

The purpose of this work was to evaluate the in vitro possibilities of ampicillin-ceftriaxone combinations for 10 Enterococcus faecalis strains with high-level resistance to aminoglycosides (HLRAg) and to assess the efficacy of ampicillin plus ceftriaxone, both administered with humanlike pharmacokinetics, for the treatment of experimental endocarditis due to HLRAg E. faecalis. A reduction of 1 to 4 dilutions in MICs of ampicillin was obtained when ampicillin was combined with a fixed subinhibitory ceftriaxone concentration of 4 µg/ml. This potentiating effect was also observed by the double disk method with all 10 strains. Time-kill studies performed with 1 and 2 µg of ampicillin alone per ml or in combination with 5, 10, 20, 40, and 60 µg of ceftriaxone per ml showed a >= 2 log10 reduction in CFU per milliliter with respect to ampicillin alone and to the initial inoculum for all 10 E. faecalis strains studied. This effect was obtained for seven strains with the combination of 2 µg of ampicillin per ml plus 10 µg of ceftriaxone per ml and for six strains with 5 µg of ceftriaxone per ml. Animals with catheter-induced endocarditis were infected intravenously with 108 CFU of E. faecalis V48 or 105 CFU of E. faecalis V45 and were treated for 3 days with humanlike pharmacokinetics of 2 g of ampicillin every 4 h, alone or combined with 2 g of ceftriaxone every 12 h. The levels in serum and the pharmacokinetic parameters of the humanlike pharmacokinetics of ampicillin or ceftriaxone in rabbits were similar to those found in humans treated with 2 g of ampicillin or ceftriaxone intravenously. Results of the therapy for experimental endocarditis caused by E. faecalis V48 or V45 showed that the residual bacterial titers in aortic valve vegetations were significantly lower in the animals treated with the combinations of ampicillin plus ceftriaxone than in those treated with ampicillin alone (P < 0.001). The combination of ampicillin and ceftriaxone showed in vitro and in vivo synergism against HLRAg E. faecalis.

* Corresponding author. Mailing address: Servei de Malalties Infeccioses, Hospital General Vall d'Hebron, Hospitals Vall d'Hebron, Avda. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. Phone: 34.93.4894033. Fax: 34.93.2746057. E-mail: gavalda{at}hg.vhebron.es.

Antimicrobial Agents and Chemotherapy, March 1999, p. 639-646, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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