In Vitro Synergism of Penicillin and Ceftriaxone against Enterococcus faecalis

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.

Penicillin plus Ceftriaxone versus Ampicillin plus Ceftriaxone Synergistic Potential against Clinical Enterococcus faecalis Blood Isolates

“…Only one other in vitro study has been published to date, which also compared checkboard synergy of ampicillin+ceftriaxone versus penicillin+ceftriaxone among 28 clinical E. faecalis blood isolates from Germany and one wild-type isolate (ATCC 29212) ( 19 ). The ceftriaxone concentrations utilized included the free plasma trough concentrations for a 2 g IV q12h, 4 g IV q24h, and 2 g IV q24h regimens, which were 4, 1.5, and 1 μg/L, respectively ( 19 ).…”

“…Only one other in vitro study has been published to date, which also compared checkboard synergy of ampicillin+ceftriaxone versus penicillin+ceftriaxone among 28 clinical E. faecalis blood isolates from Germany and one wild-type isolate (ATCC 29212) ( 19 ). The ceftriaxone concentrations utilized included the free plasma trough concentrations for a 2 g IV q12h, 4 g IV q24h, and 2 g IV q24h regimens, which were 4, 1.5, and 1 μg/L, respectively ( 19 ). Conversely, we utilized a free steady-state plasma concentration of 17.2 μg/mL based on clinical pharmacokinetic data for a 2 g IV q12h regimen, where the extrapolated trough would be 9.13 μg/mL versus the 4 μg/mL utilized by Thieme et al ( 19 , 23 ).…”

“…The ceftriaxone concentrations utilized included the free plasma trough concentrations for a 2 g IV q12h, 4 g IV q24h, and 2 g IV q24h regimens, which were 4, 1.5, and 1 μg/L, respectively ( 19 ). Conversely, we utilized a free steady-state plasma concentration of 17.2 μg/mL based on clinical pharmacokinetic data for a 2 g IV q12h regimen, where the extrapolated trough would be 9.13 μg/mL versus the 4 μg/mL utilized by Thieme et al ( 19 , 23 ). The difference in concentration is likely due to the variability in patient pharmacokinetics but should be considered when interpreting the in vitro synergy results ( 23 – 25 ).…”

“…Clinical data is limited in supporting the utilization of penicillin+ceftriaxone ( 10 , 11 , 16 , 17 ). A comparison of penicillin+ceftriaxone in vitro synergy to ampicillin+ceftriaxone has only been assessed in checkboard assays, which are limited due to the wide variability in result interpretation ( 17 – 19 ). Synergy assessment via in vitro time-kill experiments have not yet been reported.…”

Ampicillin Plus Ceftriaxone Combined Therapy for Enterococcus faecalis Infective Endocarditis in OPAT

“…Firstly, it has been assumed that the synergistic activity exhibited by AC [ 14 , 15 ] is preserved in BC combination [ 20 ]. However, recent studies have shown poor correlation between AC and BC synergistic activity and lower rates of this interaction with BC in E. faecalis clinical strains [ 21 , 22 ]. Secondly, ceftriaxone dose regimen adjustment for OPAT entails the same difficulty shown in the AC regimen.…”