Ampicillin and ceftriaxone as first line therapy for enterococcal endocarditis - I don't think so!

Please read no further if you are from Barcelona. You have made up your mind already on this topic!

For those of you with an open mind, I would like to question the opinion that ampicillin and ceftriaxone should be first line therapy for enterococcal endocarditis.

We have all seen the elderly patient with a prosthetic heart valve and Enterococcus faecalis in their blood. I love these consults because: (a) I know ID input can add a lot to the management of these infections, and (b) I know we are in the long haul and so I will get to know the patient well. But I also groan a little when I get the call because I know we are in for a difficult time - problems include "too old and sick for valve replacement surgery", there is real mortality associated with this infection, and yes, these are the patients in whom aminoglycoside use can be challenging.

For those of you who had the pleasure of knowing Bob Moellering, you will recall he was the pioneer of understanding that enterococcal endocarditis was difficult to treat with ampicillin alone. He showed that ampicillin and gentamicin was a frequently synergistic combination vs E. faecalis. It was these studies that led to recommendations that ampicillin plus gentamicin should be used for enterococcal endocarditis.

A good overview of Bob Moellering's work on antibiotics for Enterococcus can be found here:

Moellering RC Jr.
J Antimicrob Chemother. 1991 Jul;28(1):1-12.


Subsequently, research in Barcelona has shown that ampicillin and ceftriaxone are also synergistic vs. E. faecalis and that this combination may have potential utility for enterococcal endocarditis. A number of observational studies have been performed in Spain showing apparently good clinical outcomes when ampicillin and ceftriaxone are used for enterococcal endocarditis. These have been systematically reviewed very nicely here:

Peterson SC, Lau TTY, Ensom MHH.
Ann Pharmacother. 2017 Jun;51(6):496-503.
PMID: 28166656

It seems to be it is high time to perform an RCT to determine if ampicillin and ceftriaxone is just as good as ampicillin and gentamicin for enterococcal endocarditis. I don't believe we should be in a position to merely accept observational studies on face value. An RCT such as I propose would require a large scale cooperative study as individual centers would have few patients per year. But, it would be a study worth doing to answer an important clinical question. 

Who is interested in taking part?


  1. Hi David

    Well done on the blog

    This is an important issue

    Unfortunately for many of our colleagues, not using aminoglycosides has become “irresistible”
    (Munita JM et al. Clin Infect Dis 2013; 56:1269–72.)

    I draw readers attention to this letter
    (in response to the Spanish series by Fernández-Hidalgo et al. Clin Infect Dis 2013; 56:1261–8.)

    Gelfand MS, Cleveland KO. Combination therapy for enterococcal endocarditis. Clin Infect Dis 2013;57(5):767–7.
    “Currently, available evidence does not clearly support the inferiority of high- dose ampicillin monotherapy in enterococcal endocarditis, and such therapy may be appropriate in select patients.”

    The authors point out that combination therapy using ampicillin plus ceftriaxone has not been compared with ampicillin monotherapy in the treatment of endocarditis due to E. faecalis in recent studies.

    They note that early studies which demonstrated poor efficacy (e.g. Geraci JE, & Martin WJ. Circulation 1954; 10:173–94) used low doses and short courses of penicillin G, and valve replacement surgery was not yet available, which make the results difficult to compare with the current era.

    They comment that prolonged ceftriaxone therapy may not be desirable (e.g. C dif, ESBL)

    They suggest that using large doses of ampicillin by either intermittent or continuous infusions +/- gentamicin (possibly short course therapy as proposed by Scandinavian researchers) may be effective.

    Of course, due to the common scenario of high level aminoglycoside resistance, we are often unable to use synergistic ahminoglycosides (and some of us have elected to use the unproven combination therapy of high dose amp/penicillin + prayer).

    Look forward to reading more antibiotic controversies.

    Tony Korman
    Monash Infectious Diseases

  2. Many thanks for your comments Tony. I agree!


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