Ampicillin plus Ceftriaxone for Enterococcal Endocarditis

By Dean L. Winslow, MD, FACP, FIDSA, Chairman, Department of Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine, Associate Editor of Infectious Disease Alert. Dr. Winslow is a consultant for Siemens Diagnostic.

Synopsis: A nonrandomized, observational, comparative multicenter cohort study was conducted at 17 European medical centers. Patients treated with ampicillin+ceftriaxone (AC) were generally more ill at baseline than patients treated with ampicillin+gentamicin (AG). Despite this there was no difference in mortality or treatment failure between the groups. Interruption of treatment due to adverse events was more frequent in the AG-treated patients, mainly due to new-onset renal failure.

Source: Fernandez-Hidalgo N, et al. Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating Enterococcus faecalis infective endocarditis. Clin Infect Dis 2013; 56: 1261-8.

This large multicenter observational study reports on the results of treatment of patients with Enterococcus faecalis infective endocarditis (IE) with either AC (n=159) or AG (n=87). Primary outcome measures were death during treatment or at 3 month follow up, treatment failure, relapse, and adverse events requiring treatment withdrawal. A larger proportion of AC-treated patients had previous chronic kidney disease (CKD) than AG treated patients (33% vs. 16%) and cancer (18% vs. 7%). There were no differences in mortality on treatment between the groups (22% vs. 21%) or at 3 months after treatment (8% vs. 7%), treatment failure (1% vs. 2%) or in relapses (3% vs. 4%). However treatment interruption due to adverse events was much more frequent in AG-treated patients than in patients receiving AC (25% vs. 1%). This was almost entirely due to new onset renal failure (>= 25% increase in serum creatinine above baseline; 23% vs. 0%).


IE due to Enterococcus remains one of the most challenging infections encountered by ID specialists. The organism itself (in contrast to most streptococci and staphylococci) is inhibited but not efficiently killed by cell wall-active antibiotics, rendering these agents essentially bacteriostatic against enterococci. It was shown by Bob Moellering in the 1960’s that aminoglycosides (which are not active by themselves at achievable serum concentrations vs. streptococci) result in synergistic bacterial killing when combined with cell wall-active agents. Since bacteria trapped in the dense fibrin-platelet matrix of the vegetation are protected from phagocytosis by neutrophils, the mainstay of therapy of IE due to enterococci has been penicillin, ampicillin or vancomycin in combination with an aminoglycoside, administered for 4-6 weeks. While cure rates are high with these regimens, the nephrotoxicity and ototoxicity of these aminoglycoside-containing regimens is considerable.

Recently some data have suggested that as little as 2 weeks of combination therapy followed by 2-4 weeks of single agent therapy with a cell wall active agent result in high cure rates. However the toxicity of just 2 weeks of aminoglycoside treatment is significant. In addition, aminoglycosides only are effective in synergy with cell wall-active agents if the isolate of enterococcus does not display high-level resistance to that particular aminoglycoside. In vitro data suggest that certain B-lactam agents (including ceftriaxone) in combination with penicillin or ampicillin result in enhanced killing vs. enterococci. A small case series of patients with IE due to high-level aminoglycoside-resistant enterococcus suggested that ampicillin plus ceftriaxone provides effective therapy in vivo as well.1 This large non-randomized trial suggests that ampicillin plus ceftriaxone is as effective as traditional aminoglycoside-containing regimens with significantly less toxicity for all cases of E. faecalis IE. Clearly prospective randomized trials are in order.


1. Gavalda J, et al. Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone. Ann Int Med 2007; 146: 574-9.