A literature review of combination antibiotic therapy for Enterococcus faecalis bloodstream infections for infective endocarditis, published in Clinical Infectious Diseases, found that there is critical need for novel drug combinations and dosing strategies to improve efficacy and suppress the emergence of enterococcal resistance to β-lactams.

The review authors identified studies via PubMed and Embase searches, using the following keywords in ≥1 combinations with E faecalis: infective, endocarditis, bacteremia, bloodstream, infection, treatment, guideline, antibiotic, combination, synergy, resistant, biofilm, clinical, diagnosis, epidemiology, in vitro, in vivo, simulated endocardial vegetation, experimental, and β-lactamase. No limitations on publication date were used.

The authors found that the rise in resistance to aminoglycoside-containing regimes and the availability of less nephrotoxic therapies led to the emergence of new treatments, especially double β-lactam therapies.

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“Double β-lactam therapies have emerged as a novel strategy in the treatment of serious high-inoculum enterococcal infections due to their favorable side effect profiles and tolerability during long-term use,” noted the authors. At this time, however, ampicillin plus ceftriaxone is the sole combination β-lactam option supported by clinical data and is not without risk. Ampicillin plus ceftriaxone therapy is a known independent risk factor for Clostridium difficile infections, and several clinical and observational studies conclude it to be a major risk factor for vancomycin-resistant E faecium infection, including bacteremia.

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Studies using several novel β-lactam combinations determined that ampicillin plus ceftriaxone activity is similar to ampicillin plus ceftaroline and ampicillin plus cefepime, and both these are not associated with vancomycin-resistant E faecium infection. However, the authors caution, “their utilization necessitates careful evaluation for safety and development of resistance.” Further, they highlight the need to research novel combinations and dosing strategies that will improve efficacy and suppress resistance.


Beganovic M, Luther MK, Rice LB, Arias CA, Rybak MJ, LaPlante KL. A review of combination antimicrobial therapy for Enterococcus faecalis bloodstream infections and infective endocarditis [published online January 30, 2018]. Clin Infect Dis. doi: 10.1093/cid/ciy064