Efficacy of ampicillin plus ceftriaxone in treatment of experimental endocarditis due to Enterococcus faecalis strains highly resistant to aminoglycosides

The purpose of this work was to evaluate the in vitro possibilities of ampi cillin-ceftriaxone combinations for 10 Enterococcus faecalis strains with h igh-level resistance to aminoglycosides (HLRAg) and to assess the efficacy of ampicillin plus ceftriaxone, both administered with humanlike pharmacoki netics, for the treatment of experimental endocarditis due to HLRAg E. faec alis. A reduction of 1 to 4 dilutions in MICs of ampicillin was obtained wh en ampicillin was combined with a fixed subinhibitory ceftriaxone concentra tion of 4 mu g/ml. This potentiating effect was also observed by the double disk method with all 10 strains. Time-kill studies performed with 1 and 2 mu g of ampicillin alone per ml or in combination with 5, 10, 20, 40, and 6 0 mu g of ceftriaxone per ml showed a greater than or equal to 2 log(10) re duction in CFU per milliliter with respect to ampicillin alone and to the i nitial inoculum for all 10 E. faecalis strains studied. This effect was obt ained for seven strains with the combination of 2 pg of ampicillin per ml p lus 10 mu g of ceftriaxone per ml and for six strains with 5 mu g of ceftri axone per ml. Animals with catheter-induced endocarditis were infected intr avenously with 10(8) CFU of E. faecalis V48 or 10(5) CFU of E. faecalis V45 and were treated for 3 days with humanlike pharmacokinetics of 2 g of ampi cillin 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 pharma cokinetics of ampicillin or ceftriaxone in rabbits were similar to those fo und 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 vegeta tions 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.