Ampicillin + Ceftriaxone for Treatment of Endocarditis Due to Enterococcus faecalis

Abstract & Commentary

By Robert Muder, MD, Hospital Epidemiologist, Pittsburgh VA Medical Center, Section Editor, Hospital Epidemiology, is Associate Editor for Infectious Disease Alert.

Dr. Muder does research for Aventis and Pharmacia.

Synopsis: The combination of ampicillin and ceftriaxone was effective in treatment of endocarditis due to E. faecalis. Efficacy was similar for infections involving isolates with and without high-level aminoglycoside resistance.

Source: Gavalda J et al. Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone. Ann Intern Med 2007;146:574-579.

Gavalda and colleagues reported their experience with treating 43 patients with E. faecalis endocarditis using a combination of intravenous ampicillin 2 g every 4 hours and ceftriaxone 2 g every 12 hours for 6 weeks. Twenty-one patients were infected with strains exhibiting high-level aminoglycoside resistance (HLAR) and 22 were infected with non-HLAR strains. 8/21 (38%) patients with HLAR E. faecalis endocarditis had prosthetic valve infections, as did 10/22 (45%) patients with non-HLAR infection.

3/21 patients with HLAR E. faecalis endocarditis required surgery, and 7 died during therapy; one of the deaths was due to aspiration pneumonia. All patients who died had negative blood cultures prior to death. One patient died 30 days after therapy due to complications of HIV infection. The remaining 13 patients were free of infection after 3 months of follow-up.

4/22 patients with non-HLAR E. faecalis endocarditis required surgery, and 4 died during therapy. There were 2 relapses in this group. One patient received ceftriaxone 2 g every 24 hours rather than every 12 hours; he was subsequently cured after treatment with ampicillin plus ceftriaxone 2 g every 12 hours. A patient with an aortic Dacron graft and prosthetic aortic valve suffered a fatal cerebral hemorrhage 21 days after completing therapy. Pre-mortem blood cultures were positive for E. faecalis.

In vitro assessment of synergy by time-kill method showed synergistic killing by the combination of ampicillin and ceftriaxone for all 28 isolates tested.

Commentary

E. faecalis strains are generally tolerant to penicillin and ampicillin, i.e., bacterial killing occurs only at antibiotic levels many-fold greater than the MIC. Successful treatment of E. faecalis endocarditis usually requires the combination of penicillin or ampicillin plus and aminoglycoside. The combinations result in synergistic killing of E. faecalis in vitro and in vivo. For enterococcal isolates exhibiting HLAR, synergistic killing does not occur due the presence of one of several aminoglycoside modifying enzymes. Even if the infecting strain does not exhibit HLAR, the 4-6 week course of treatment required for treatment of enterococcal endocarditis frequently results in significant aminoglycoside toxicity.

The combination of ampicillin + ceftriaxone shows synergism against E. faecalis both in vitro and in an animal model of endocarditis1,2 whether or not the strain demonstrates HLGR. Efficacy in the animal model was similar to that obtained with ampicillin + aminoglycoside. Addition of an aminoglycoside to the combination of ampicillin + gentamicin did not improve efficacy.

Although not a randomized controlled trial, the results reported by Gavalda and colleagues are similar to those obtained using the combination of ampicillin + an aminoglycoside for the treatment of non-HLAR E. faecalis endocarditis. Thus ampicillin + ceftriaxone may be reasonably considered to be first line therapy for HLAR E. faecalis. Other potential therapies include linezolid and daptomycin; clinical experience in treating E. faecalis endocarditis with these agents is more limited. Nearly all strains of E. faecalis are resistant to quinupristin/dalfopristin.

The combination of ampicillin + ceftriaxone is a rational second-line combination for treatment of non- HLAR E. faecalis endocarditis in patients at high risk for gentamicin toxicity, such as those with pre-existing renal insufficiency.

Several cautions are in order. The first is that this study was not randomized and involved a relatively small number of patients. The second is that ampicillin/ceftriaxone synergy may not be present if the strain is resistant to ampicillin.3 Finally, this study should not be extrapolated to treatment of E. faecium endocarditis, as E. faecium is less susceptible to ampicillin than E. faecalis.

References:

  1. Gavalda J et al. Efficacy of ampicillin plus ceftriaxone in treatment of experimental endocarditis due to Enterococcus faecalis strains highly resistant to aminoglycosides. Antimicrob Agents Chemother 1999;43:639-646.
  2. Gavalda J et al. Efficacy of ampicillin combined with ceftriaxone and gentamicin in the treatment of experimental endocarditis due to Enterococcus faecalis with no high-level resistance to aminoglycosides. J Antimicrob Agents Chemother 2003;52:514-517.
  3. Mainardi JL et al. Synergistic effect of amoxicillin and cefotaxime against Enterococcus faecalis. Antimicrob Agents Chemother 1995:39:1984-1987.