Combination Therapy for Enterococcal Bacteremia: Is 2 better than 1?

Part of the Enterococci series

Different bosses, different habits. During my residency, one particular consultant consistently treated Enterococcus faecalis bacteremia with both ampicillin and ceftriaxone. While this consultant was known for his antimicrobial polypharmacy (much to the consternation of the antimicrobial stewardship team), I just accepted his approach at the time. In what follows, I want to critically evaluate this practice by addressing the ensuing questions:

1. Why it might be a good idea to treat E. faecalis with combination therapy?

2. What is the clinical evidence for combination therapy in E. faecalis endocarditis?

3. What is the clinical evidence for combination therapy in isolated E. faecalis bacteremia?

1. Why it might be a good idea to treat E. faecalis with combination therapy?

Enterococci are considered “less virulent” microorganisms (1). However, through their close association with humans, they have acquired some interesting features such as the possibility to form biofilms and to attach to most human epithelia in the gut and urinary tract (1-2). Moreover, enterococci are tolerant to their principal antibiotic therapies (3), vancomycin and beta-lactams. This means that a large discrepancy is present in vitro between the minimal inhibitory concentration and the concentration required to reduce the initial inoculum more than 99.9% at 24 hours (1). Consequently, most antibiotic therapy are only bacteriostatic (4) and might be insufficient to completely cure a bloodstream infection by E. faecalis. Taken all these previous factors into consideration, a combination of antibiotics might be desirable to optimize the treatment for enterococcal bacteremia.

Currently, two common combination therapies are commonly recognized to treat E. faecalis endocarditis, ampicillin - gentamicin and ampicillin - ceftriaxone (note that amoxicillin and ampicillin are used interchangeably in the text and are considered equal options).

a. Ampicillin-gentamicin

This is the oldest combination therapy for E. faecalis, which saw the daylight in the early days of antibiotic therapy, when penicillin monotherapy frequently failed (5). Aminoglycosides poorly penetrate the enterococcal cell wall and thus cannot sufficiently inhibit their ribosomal target. Conversely, in combination with a cell wall-active agent, such as vancomycin or ampicillin, bacterial permeability increases dramatically (7). This synergy has been observed in vitro and in several animal studies (5)

Reliance on this combination therapy, however, presents some major problems:

• The clinical benefit of the combination ampicillin - gentamicin has never been thoroughly established (5). The main argument to continue this combination is historical, as the observational data from the 1950s shouldn’t convince anyone (5).

• High-level aminoglycoside resistance has become increasingly common (up to 63% in some regions) (2), often due to modifying enzymes or target modification (3). In these cases, combination ampicillin and gentamicin becomes ineffective (3).

• This synergistic effect cannot be extrapolated to other aminoglycosides such as amikacin and kanamycin (3).

• The optimal dosing regimen for gentamicin remains unclear. Additionally, its use is associated with nephrotoxicity in many patients (8).

b. Ampicillin-ceftriaxone

Enterococci are intrinsically resistant to cephalosporins due to the presence of low-affinity penicillin-binding proteins in combination with other genetic determinants (1,3). Nevertheless, in vitro data from the 1990s demonstrated a synergistic effect between amoxicillin and certain cephalosporins. Most likely, the underlying mechanism involves a more complete saturation of all penicillin-binding proteins (PBPs): PBP 4 and 5 by ampicillin and PBP 2 and 3 by ceftriaxone (5). This in vitro synergy has been demonstrated for ceftriaxone and may also occur for ceftaroline and cefepime (2).

Limitations:

• In vitro synergy with third generation cephalosporins was not observed when bactericidal concentrations of amoxicillin were used (11). Additionally, in a rabbit endocarditis model, combination therapy with ceftriaxone did not enhance sterilization of the aortic valve, unlike combination with gentamicin (11).

• This combination cannot be used for E. faecium bacteremia, as these isolates are mostly ampicillin-resistant (5,9).

• Since ceftriaxone is predominantly excreted in the bile, it may promote E. faecium colonization (including vancomycin-resistant enterococci).

2. What is the clinical evidence for combination therapy in E. faecalis endocarditis?

The current guidelines recommend that E. faecalis endocarditis can be treated with ampicillin plus ceftriaxone for 6 weeks OR ampicillin plus a 2-week course of gentamicin (5,9), though some guidelines prefer ampicillin-ceftriaxone due to its better safety profile (9).

Both combination therapies are considered equally effective, which is supported by some retrospective cohort studies. A systematic review from 2021, including a total of 599 patients with E. faecalis endocarditis, concluded that ampicillin plus ceftriaxone was non-inferior to ampicillin plus gentamicin (10). However, the ampicillin-ceftriaxone group had lower rates of nephrotoxicity and fewer drug withdrawals (5).

Nevertheless, it remains unclear whether combination therapy is ultimately necessary. As some authors have noted, the similar efficacy of both combination therapies could also be explained if both didn’t provide any noticeable benefit (12). Beyond historical data in support for gentamicin (5), evidence of superiority of combination therapy versus monotherapy is extremely limited:

A) A French multicenter, retrospective study included a total of 279 patients with E. faecalis endocarditis, of whom nine received amoxicillin monotherapy (13). Relapse and mortality rates were significantly higher in this group than among those receiving combination therapy. However, cautious interpretation is warranted. After all, the data also show that all relapses in the monotherapy occurred in those who finished their six week antibiotic therapy. Additionally, the lowest mortality of all people completing their treatment was observed in the amoxicillin monotherapy group of all patients completing their treatment. Clearly, no strong conclusions can be established due to the small number of patients and the significant biases (5,11).

B) An Austrian, single-center, retrospective study, included 78 episodes of E. faecalis endocarditis over 25 years, of which 20 were treated with aminopenicillin monotherapy (11). No significant differences in mortality or relapse rate were observed between aminopenicillin monotherapy and combination therapy.

My view: E. faecalis endocarditis is a serious infection for which clear guidelines exist, so I currently feel compelled to continue treating it with a combination of ampicillin/amoxicillin and ceftriaxone. However, the evidence supporting this approach is far from conclusive. Therefore, as a first step, it is of the utmost importance to publish retrospective data comparing monotherapy with combination therapy. Also, in case of ceftriaxone toxicity, I would feel quite safe continuing high-dose aminopenicillin as monotherapy.

3. What is the clinical evidence for combination therapy in isolated E. faecalis bacteremia?

Isolated E. faecalis bacteremia occurs frequently (11) but should only be diagnosed after a thorough workup. The clinical evidence for combination therapy in this setting is even more limited than for E. faecalis endocarditis (1,4,6). Unfortunately, the clinical evidence stems completely from small, retrospective studies and thus is intrinsically biased (4). One notable study from Bern, however, used a before-after design due to the fact that adjunctive gentamicin in enterococcal bacteremia was no longer recommended from 2009 (14). Over 17 years, 154 episodes of enterococcal bloodstream infections were included in neutropenic patients (although E. faecalis was the causative organism in only a quarter of all cases). Combination therapy with gentamicin did not improve survival or reduce persistence of bloodstream infection.

Notwithstanding the lack of evidence for combination therapy in enterococcal blood stream infections, some authors recommend its use in certain circumstances:

I) For community-acquired infections (6).More insights on this subject are expected by the end of 2025, when a subgroup analysis of the BALANCE trial specifically for enterococcal bacteremia should be published (15). Although this trial primarily compared 7 versus 14 days of antibiotic therapy, it included only community-acquired infections and thus might provide a better idea about optimal treatment of these infections (16).

II) For persistent bacteremia without an identifiable focus (1). Definitions vary (1); for example, persistent bacteremia may be defined as positive blood cultures despite appropriate antibiotic treatment after 5 days (6).

My view: Currently, there is no evidence to support combination therapy for isolated E. faecalis bacteremia and given the potential for harm, I will continue to use monotherapy. In the coming years, I believe that, in addition to the BALANCE trial subgroup analysis, some general principles may also be extrapolated from SNAP, a large S. Aureus bacteremia trial.

References:

 1. Rogers R, Rice LB. State-of-the-Art Review: Persistent Enterococcal Bacteremia. Clin Infect Dis. 2024 Jan 25;78(1):e1-e11.

 2. Beganovic M, Luther MK, Rice LB, et al. A Review of Combination Antimicrobial Therapy for Enterococcus faecalis Bloodstream Infections and Infective Endocarditis. Clin Infect Dis. 2018 Jul 2;67(2):303-309.

 3. Kristich CJ, Rice LB, Arias CA. Enterococcal Infection—Treatment and Antibiotic Resistance. 2014 Feb 6. In: Gilmore MS, Clewell DB, Ike Y, Shankar N, editors. Enterococci: From Commensals to Leading Causes of Drug Resistant Infection [Internet]. Boston: Massachusetts Eye and Ear Infirmary; 2014.

 4. Bartash R, Nori P. Beta-lactam combination therapy for the treatment of Staphylococcus aureus and Enterococcus species bacteremia: A summary and appraisal of the evidence. Int J Infect Dis. 2017 Oct;63:7-12.

 5. McDonald EG, Aggrey G, Aslan AT, et al. Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement. JAMA Netw Open. 2023 Jul 3;6(7):e2326366.

 6. Rosselli Del Turco E, Bartoletti M, Dahl A, et al. How do I manage a patient with enterococcal bacteraemia? Clin Microbiol Infect. 2021 Mar;27(3):364-371.

 7. Pericás JM, Zboromyrska Y, Cervera C, et al. Enterococcal endocarditis revisited. Future Microbiol. 2015;10(7):1215-40.

 8. Fernández-Hidalgo N, Almirante B, Gavaldà J, et al. Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating enterococcus faecalis infective endocarditis. Clin Infect Dis. 2013 May;56(9):1261-8.

 9. Delgado V, Ajmone Marsan N, de Waha S, et al. 2023 ESC Guidelines for the management of endocarditis. Eur Heart J. 2023 Oct 14;44(39):3948-4042.

 10. Mirna M, Topf A, Schmutzler L, et al. Time to abandon ampicillin plus gentamicin in favour of ampicillin plus ceftriaxone in Enterococcus faecalis infective endocarditis? A meta-analysis of comparative trials. Clin Res Cardiol. 2022 Oct;111(10):1077-1086.

 11. Schubert L, Chen RY, Weiss-Tessbach M, et al. 25 years of experience on the management of enterococcal infective endocarditis an observational study. Infection. 2025 Feb;53(1):467-474.

 12. Koehler P, Jung N, Cornely OA, et al. Combination Antimicrobial Therapy for Enterococcus faecalis Infective Endocarditis. Clin Infect Dis. 2019 Aug 16;69(5):900.

 13. Danneels P, Hamel JF, Picard L, et al. Impact of Enterococcus faecalis Endocarditis Treatment on Risk of Relapse. Clin Infect Dis. 2023 Jan 13;76(2):281-290.

 14. Jent P, Thalmann L, Pabst T, et al. Adjunctive gentamicin did not improve outcome of enterococcal bacteraemia in neutropenic patients: a propensity scored matched study. Infect Dis (Lond). 2019 Jun;51(6):409-416.

 15. Personal correspondence with the author

 16. Daneman N, Rishu A, Pinto R, et al. Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. N Engl J Med. 2025 Mar 13;392(11):1065-1078.