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Background Synergistic ampicillin plus ceftriaxone (AC) for Enterococcus faecalis infective endocarditis outpatient use is precluded by ampicillin’s poor room temperature stability. Penicillin has superior stability and has been combined with ceftriaxone (PC), however there is a lack of studies to demonstrate synergy. Methods AC and PC were evaluated, in duplicate, for synergy utilizing 24-hour in vitro time-kill assays with a starting inoculum of 106 colony forming units (CFU)/mL. Six clinical E. faecalis blood isolates and one wild-type E. faecalis isolate (JH2-2) were included. All isolates were susceptible to ampicillin and penicillin, with minimum inhibitory concentrations (MICs) ranging from 0.5-1 µg/mL and 2-4 µg/mL, respectively. Ampicillin and penicillin were tested at subinhibitory concentrations (0.25x and 0.5xMIC) as monotherapy and in combination with ceftriaxone average steady state concentrations for a dose of 2g IV q12hr (CPss 17.2 µg/mL), as all ceftriaxone MICs were high due to intrinsic resistance (MICs 128-2048 µg/mL). Synergy was defined as a ≥ 2 log10 decrease in CFU/mL at 24 hours from the most active single agent. Results An average increase in bacterial density from the starting inoculum was observed for all isolates against ampicillin 0.25xMIC alone, penicillin 0.25x and 0.5xMIC alone, and ceftriaxone alone (+1.60 ± 0.62, +1.91 ± 0.37, +1.48 ± 0.42, and +1.84 ± 0.46 log10 CFU/mL, respectively) [Table 1]. Ampicillin 0.5xMIC alone average increase in bacterial density from starting inoculum for all but two isolates (e2008 and e2009) was +1.21 ± 0.59 log10 CFU/mL. Isolates e2008 and e2009 were the only isolates with a higher penicillin MIC of 4 µg/mL, and did not display synergy for all AC and all PC combinations. AC synergy was observed for all other isolates, with only one isolate (e2012) displaying synergy at 0.5xMIC. PC synergy was observed for four isolates at 0.5xMIC (-3.47 ± 0.94 log10 CFU/mL) and for only one isolate (e2014) at 0.25xMIC but the change in bacterial density was -0.38 ± 0.24 log10 CFU/mL. Conclusion PC synergy against E. faecalis was observed with higher penicillin concentrations. AC and PC did not demonstrate synergy against isolates with a higher penicillin MIC of 4 µg/mL. Further research is warranted to better understand PC synergy against E. faecalis. Disclosures All Authors: No reported disclosures |
