In Vitro Synergism of Penicillin and Ceftriaxone against Enterococcus faecalis.

Lara Thieme,Mathias W Pletz,Oliwia Makarewicz,Eamon Duffy,Simon Briggs

doi:10.3390/microorganisms9102150

Abstract

Enterococcus faecalis infective endocarditis is commonly treated with intravenous ampicillin/ceftriaxone combination therapy. Ampicillin, however, is unsuitable for outpatient parenteral antibiotic therapy (OPAT) regimens due to its instability in 24 h continuous infusors, and has been successfully replaced by benzylpenicillin used together with ceftriaxone in a few small case series. Since in vitro synergy data of penicillin/ceftriaxone against E. faecalis are still lacking, checkerboard assays were performed for 28 clinical E. faecalis isolates and one laboratory standard strain. Synergistic effects (both lowest and median FICI) were observed for penicillin/ceftriaxone in 15/29 isolates, while ampicillin/ceftriaxone exhibited synergism in 22/29 isolates. For isolates with ceftriaxone MICs ≤ 256 mg/L, the addition of free ceftriaxone trough concentrations to penicillin or ampicillin resulted in comparable synergistic effects for both combinations. In contrast, for isolates with ceftriaxone MICs ≥ 512 mg/L free ceftriaxone trough concentrations were only sufficient to exhibit synergistic effects in combination with ampicillin, but not penicillin. This study suggests that benzylpenicillin/ceftriaxone would be expected to be suitable for the OPAT treatment of enterococcal endocarditis for E. faecalis isolates with ceftriaxone MICs ≤ 256 mg/L. However, combination therapy would be expected to provide no advantage over benzylpenicillin monotherapy for isolates with ceftriaxone MICs ≥ 512 mg/L. Further investigation is required to analyse the relationship between ceftriaxone susceptibility and penicillin/ceftriaxone synergy, especially for isolates with ceftriaxone MICs of 64 to 512 mg/L.

Highlights

Enterococcus faecalis is an increasingly common cause of infective endocarditis (IE)and should be treated with prolonged synergistic, bactericidal antibiotic combination therapy [1,2]
Ampicillin, amoxicillin, or benzylpenicillin combined with IV gentamicin for gentamicin susceptible isolates, or IV ampicillin combined with IV ceftriaxone for both high-level aminoglycoside-resistant (HLAR) and non-HLAR isolates [2,3]
While ampicillin/ceftriaxone has been proposed as an Outpatient Parenteral Antibiotic Therapy (OPAT) regimen for E. faecalis IE (EFIE) utilising either elastomeric continuous infusors or programmable pumps for the delivery of ampicillin [7], the literature shows conflicting results regarding the stability of ampicillin in elastomeric continuous infusors [8,9,10,11]

Summary

Introduction

Enterococcus faecalis is an increasingly common cause of infective endocarditis (IE)and should be treated with prolonged synergistic, bactericidal antibiotic combination therapy [1,2]. Contemporary treatment guidelines recommend the use of intravenous (IV). The abovementioned guideline-recommended regimens for the treatment of E. faecalis IE (EFIE) may be challenging to administer via an OPAT service due to the multiple doses. While ampicillin, which cannot be applied orally for reasons of bioavailability, could theoretically be replaced by orally administered amoxicillin, the clinical evidence supporting oral antibiotic regimens for treating EFIE is scarce. The use of oral antibiotics as part of the treatment of endocarditis has only been assessed in one trial [12] that enrolled a tightly defined group of patients with left-sided endocarditis who were transitioned to oral regimens. The patients with EFIE were treated with a variety of oral antibiotic combinations, the most common of which were amoxicillin /moxifloxacin, amoxicillin/linezolid, and amoxicillin/rifampicin.

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Conclusion