Comparison of ceftriaxone versus ceftaroline in combination with ampicillin or penicillin against Enterococcus...

Enterococcus faecalis infective endocarditis treatment with ampicillin plus ceftriaxone has not changed the mortality rates by over 30%. We identified borderline-penicillin-resistant, ampicillin-susceptible E. faecalis (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 E. faecalis 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) E. faecalis 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 E. faecalis, including borderline-PRASEF.IMPORTANCEThe preferred therapy for treatment of Enterococcus faecalis 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 E. faecalis (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 Clostridoides difficile 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.