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

Abstract

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 10E. 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. faecalisV45 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 HLRAgE. faecalis.

Medical treatment of prosthetic vascular graft infections: Review of the literature and proposals of a Working Group

“…Experimental data have shown that the ampicillin + ceftriaxone combination may act synergistically when used in the treatment of experimental endocarditis caused by Enterococcus faecalis [120,121]. Human clinical data also appear to confirm this [122,123].…”

Diversity of enterococcal species and characterization of high-level aminoglycoside resistant enterococci of samples of wastewater and surface water in Tunisia

“…Standard recommended therapy for systemic enterococcal infections consists in a combination of either penicillin or vancomycin with an aminoglycoside (gentamicin or streptomycin). The goal of this combination therapy is to achieve a synergistic bactericidal effect between the cell wall agent and the aminoglycoside (Gavaldà et al, 1999). However, resistance of these agents is being increasingly reported (Arias et al, 2010).…”

Medical treatment of endocarditis

“…In vitro studies have shown that combinations of cell wall-active antibiotics may be synergistic on such strains without an added aminoglycoside. This finding was demonstrated for teicoplanin-imipenem [58], ampicillin-ceftriaxone [59,60], and ampicillin-imipenem [61] on E. faecalis strains. Ampicillin, 12 g daily, plus ceftriaxone, 2 g every 12 hours, or ampicillin, 12 g daily, plus imipenem, 2 g every 24 hours in four equal doses, is now recommended for the treatment of multidrug-resistant E. faecalis IE [13••] Conceptually, double -lactam therapy could be used to treat -lactam-sensitive enterococci that are both gentamicin and streptomycin resistant [62].…”