Ceftobiprole alone versus ampicillin-ceftriaxone against borderline-penicillin-resistant, ampicillin-susceptible, and vancomycin-resistant <i>Enterococcus faecalis</i> isolates

Despite the use of recommended treatments against <i>Enterococcus faecalis</i> infective endocarditis, mortality rates remain at 30%. Penicillin-resistant, ampicillin-susceptible <i>E. faecalis</i> (PRASEF) has been associated with worsened clinical outcomes; however, a more common phenotype, borderline-PRASEF (penicillin minimum inhibitory concentration [MIC] 4-8 µg/mL), decreases the activity of ampicillin-ceftriaxone <i>in vitro</i>. Ceftobiprole presents a promising alternative against borderline-PRASEF and also has shown activity against vancomycin-resistant <i>E. faecalis</i> (VREfs). The ceftobiprole MIC distribution was determined via broth microdilution for 78 <i>E. faecalis</i> clinical blood isolates, including 71 borderline-PRASEF. Ceftobiprole activity alone was compared to ampicillin-ceftriaxone via <i>in vitro</i> 24-hour time-kill assays against 30 <i>E. faecalis</i> isolates, 24 of which were borderline-PRASEF and 15 were VREfs. Ceftobiprole and ceftriaxone were tested at physiologic concentrations (<i>fCpss</i> 13.9 µg/mL and 17.2 mcg/mL, respectively) and ampicillin at subinhibitory concentrations (0.25 × MIC and 0.5 × MIC). Isolates where ceftobiprole alone had limited activity were tested against ceftobiprole-ampicillin. Ceftobiprole maintained activity against borderline-PRASEF compared to ampicillin-ceftriaxone. Ceftobiprole also demonstrated more activity against VREfs isolates and isolates with an elevated ceftobiprole MIC ≥16 µg/mL, compared to ampicillin-ceftriaxone. Ceftobiprole did not achieve ≥2 log₁₀ CFU/mL kill in six isolates but was able to achieve this once combined with ampicillin. When tested at ampicillin inhibitory concentrations, ceftobiprole-ampicillin activity trended towards antagonism in two isolates. Overall, ceftobiprole alone had greater activity compared to ampicillin-ceftriaxone, and there may be a potential role of ceftobiprole combination therapy in certain isolates.