Comparison of ceftriaxone versus ceftaroline in combination with ampicillin or penicillin against <i>Enterococcus faecalis</i>

<i>Enterococcus faecalis</i> infective endocarditis treatment with ampicillin plus ceftriaxone has not changed the mortality rates by over 30%. We identified borderline-penicillin-resistant, ampicillin-susceptible <i>E. faecalis</i> (borderline-PRASEF; penicillin MIC 4-8 µg/mL, breakpoint ≤8 µg/mL) isolates that have decreased ampicillin-ceftriaxone activity, which is present in 25% of isolates in New York City. Alternatively, ceftaroline is more active against <i>E. faecalis</i> than ceftriaxone. We compared the activity of ampicillin or penicillin plus ceftriaxone or ceftaroline against nine borderline-PRASEF and seven penicillin-susceptible (penicillin MIC ≤2 µg/mL) <i>E. faecalis</i> isolates via 24 h time-kill assays. MICs were obtained via broth microdilution per CLSI. Ampicillin, penicillin, and ceftaroline were tested at subinhibitory concentrations (0.25 × MIC and 0.5 × MIC) and ceftriaxone at the free plasma steady-state concentration (17.2 µg/mL). All experiments were completed in duplicate with a starting inoculum of 10⁶ CFU/mL. After 24 h, antimicrobial activity was measured as ≥2-log₁₀ CFU/mL decrease from the initial inoculum. Combinations were assessed for synergy (≥2-log₁₀ CFU/mL decrease from the most active single agent). Ceftriaxone and ceftaroline MICs were more likely to be higher in borderline-PRASEF isolates compared to penicillin-susceptible isolates. Ceftaroline-based combinations more often demonstrated synergy and activity than ceftriaxone combinations. When assessed by penicillin MIC, ceftriaxone-based combinations less frequently demonstrated synergy and activity against borderline-PRASEF isolates compared to ceftaroline-based combinations. Ceftaroline-based combinations may be an effective alternative targeting <i>E. faecalis</i>, including borderline-PRASEF.IMPORTANCEThe preferred therapy for treatment of <i>Enterococcus faecalis</i> infective endocarditis is ampicillin plus ceftriaxone; however, there is a need for alternative treatments given the unchanged mortality rates exceeding 30%. Recent data show decreased ampicillin-ceftriaxone activity against borderline-penicillin-resistant, ampicillin-susceptible <i>E. faecalis</i> (borderline-PRASEF), which is present in 25% of isolates. Ceftaroline is an alternative cephalosporin that has been explored as it does not carry the risks ceftriaxone has to increase vancomycin resistance and <i>Clostridoides difficile</i> infection. Ceftaroline also provides saturation of both essential penicillin-binding protein (PBP) 4 and non-essential PBP2/3, whereas ceftriaxone only binds to PBP2/3. The activity of ceftaroline-based combinations against borderline-PRASEF is unknown. This study demonstrates the ability of ampicillin or penicillin plus ceftaroline to maintain activity against borderline-PRASEF where ampicillin or penicillin plus ceftriaxone combination activity is limited.