Comparison of Ceftobiprole Versus Ampicillin-ceftriaxone Antibacterial Activity Against Borderline-penicillin-resistant Ampicillin-susceptible and Vancomycin-resistant Enterococcus Faecalis
Faculty Mentor
Jaclyn Cusumano and Olivia Funk
Major/Area of Research
Pharmacy (Infectious Disease)
Description
Background: Enterococcus faecalis endocarditis mortality rates exceed 30% despite the use of first-line ampicillin plus ceftriaxone therapy. We identified decreased ampicillin-ceftriaxone activity against borderline-penicillin-resistant, ampicillin-susceptible E. faecalis (borderline-PRASEF) (penicillin minimum inhibitory concentration (MIC), 4-8 μg/mL, Clinical and Laboratory Standards Institute (CLSI) breakpoint ≤8) which is present in 30% of New York City isolates. Additionally, vancomycin resistance (VRE) is rising in E. faecalis especially among borderline-PRASEF, further limiting treatment options. Ceftobiprole is a promising agent against E. faecalis, including borderline-PRASEF and VRE.
Methods: Ceftobiprole versus ampicillin-ceftriaxone was tested against 23 borderline-PRASEF isolates, 12 of which were VRE, via 24-hour time-kills assays. MICs were determined using broth microdilution in accordance with CLSI. Ampicillin was tested at subinhibitory concentrations (0.25xMIC and 0.5xMIC) and the free plasma steady state concentration (fCpSS) was used for ceftriaxone (fCpSS=17.2 μg/mL) and ceftobiprole (fCpSS=13.8 μg/ mL) based on population pharmacokinetics. Experiments were tested in duplicate with a starting inoculum of 10^6 colony-forming unit (CFU)/mL. Antibacterial activity was de- fined as ≥2-log10 CFU/mL decrease from the initial inoculum. Differences in antibacterial activity were compared between ceftobiprole versus ampicillin-ceftriaxone and between vancomycin-susceptible (VSE) and VRE isolates via Fisher’s exact test.
Conclusion: Ceftobiprole MICs ranged from 0.5 to 32 μg/mL and were more frequently ≥16 μg/mL among VRE vs. VSE isolates (50% vs. 18.2%, p=0.24). Antibacterial activity was more common with ceftobiprole alone versus ampicillin 0.25xMIC and 0.5xMIC plus ceftriaxone (73.9% vs. 4.4%, p<0.01 and 8.7%, p<0.01; respectively). When comparing vancomycin susceptibility, ceftobiprole demonstrated less activity against VRE compared to VSE iso- lates (66.7% vs. 81.8%, p=0.73). Overall, ceftobiprole more frequently demonstrated ac- tivity against borderline-PRASEF compared to ampicillin plus ceftriaxone, however ceftobiprole activity is diminished against VRE. Further research is warranted to deter- mine the role of ampicillin in combination with ceftobiprole to improve activity against VRE.
Comparison of Ceftobiprole Versus Ampicillin-ceftriaxone Antibacterial Activity Against Borderline-penicillin-resistant Ampicillin-susceptible and Vancomycin-resistant Enterococcus Faecalis
Background: Enterococcus faecalis endocarditis mortality rates exceed 30% despite the use of first-line ampicillin plus ceftriaxone therapy. We identified decreased ampicillin-ceftriaxone activity against borderline-penicillin-resistant, ampicillin-susceptible E. faecalis (borderline-PRASEF) (penicillin minimum inhibitory concentration (MIC), 4-8 μg/mL, Clinical and Laboratory Standards Institute (CLSI) breakpoint ≤8) which is present in 30% of New York City isolates. Additionally, vancomycin resistance (VRE) is rising in E. faecalis especially among borderline-PRASEF, further limiting treatment options. Ceftobiprole is a promising agent against E. faecalis, including borderline-PRASEF and VRE.
Methods: Ceftobiprole versus ampicillin-ceftriaxone was tested against 23 borderline-PRASEF isolates, 12 of which were VRE, via 24-hour time-kills assays. MICs were determined using broth microdilution in accordance with CLSI. Ampicillin was tested at subinhibitory concentrations (0.25xMIC and 0.5xMIC) and the free plasma steady state concentration (fCpSS) was used for ceftriaxone (fCpSS=17.2 μg/mL) and ceftobiprole (fCpSS=13.8 μg/ mL) based on population pharmacokinetics. Experiments were tested in duplicate with a starting inoculum of 10^6 colony-forming unit (CFU)/mL. Antibacterial activity was de- fined as ≥2-log10 CFU/mL decrease from the initial inoculum. Differences in antibacterial activity were compared between ceftobiprole versus ampicillin-ceftriaxone and between vancomycin-susceptible (VSE) and VRE isolates via Fisher’s exact test.
Conclusion: Ceftobiprole MICs ranged from 0.5 to 32 μg/mL and were more frequently ≥16 μg/mL among VRE vs. VSE isolates (50% vs. 18.2%, p=0.24). Antibacterial activity was more common with ceftobiprole alone versus ampicillin 0.25xMIC and 0.5xMIC plus ceftriaxone (73.9% vs. 4.4%, p<0.01 and 8.7%, p<0.01; respectively). When comparing vancomycin susceptibility, ceftobiprole demonstrated less activity against VRE compared to VSE iso- lates (66.7% vs. 81.8%, p=0.73). Overall, ceftobiprole more frequently demonstrated ac- tivity against borderline-PRASEF compared to ampicillin plus ceftriaxone, however ceftobiprole activity is diminished against VRE. Further research is warranted to deter- mine the role of ampicillin in combination with ceftobiprole to improve activity against VRE.