Reviewing the Synergistic Activity of Ampicillin With Cephalosporins, Carbapenems Against Enterococcus faecalis

The gram-positive bacterium Enterococcus faecalis, which is classified as part of the group D Streptococcus, inhabits the gastrointestinal tracts of humans.¹ E faecalis has been an increasingly common cause of infective endocarditis, with the preferred treatment being a combination of antibiotics.²

Jose Alexander, MD, ABMM, ABAIM, FCCM, CIC, ASCP, BCMAS, medical director for the microbiology laboratory at AdventHealth in Orlando, Florida, says that when looking at data from his institution, he approximates that 99% of Enterococcus spp. are susceptible to ampicillin (AMP), yet the antimicrobial does not respond because of poor tissue penetration and biofilm formation.

He and his team at AdventHealth wanted to look in vitro at AMP and add another agent, particularly β-lactams when looking at E faecalis infections.

“Adding another agent as a synergy that can target a different group of the penicillin-binding protein can help to actually break through and act as a true bactericidal agent,” Alexander said. “Ampicillin is a bactericidal, but it's a possibility that it is acting more as a bacteriostatic in this particular scenario where the immune system is not able to penetrate and biofilm is being formed in endocarditis.”

Alexander and his colleagues compared the activity and potential synergy between AMP with cephalosporins (ceftaroline [CPT] or ceftriaxone [CRO]) and carbapenems (ertapenem [ERTP] or imipenem [IMI]) in vancomycin-susceptible E faecalis.² Alexander presented this research at the American Society for Microbiology Microbe conference this summer.

A total of 24 vancomycin-susceptible E faecalis bacteria were obtained from various sources at his institution.² Antibiotic susceptibility testing was performed. AMP was crossed at organisms' tested minimum inhibitory concentration (MIC), whereas CPT, CRO, ERTP, and IMI were all at MIC of 1 µg/mL or less.

“The combination [of] AMP with cephalosporins demonstrated the most synergy/additive effect with AMP plus CPT at 67% (n = 16), followed by the combination of AMP and CRO at 37.5% (n = 9). AMP and carbapenem combination yielded the fewest effects, with AMP and IMI being the lowest, with no synergy observed,” Alexander et al wrote about their findings.²

In terms of his study’s limitations, Alexander acknowledges this was done in vitro and was a very small sampling, but still he points to the potential clinical application.

“I think being able to rule out the presence of antagonism, especially between these β-lactams, gives some peace of mind for clinicians when they decide to combine therapy,” Alexander said. “If they have a patient with endocarditis who is not responding and the organism is susceptible to ampicillin—and they want to implement an antagonist—this can create a synergy activity.”

And he points out this can be done safely.

“We know that even if there is no improved activity between these 2 agents, at least they are not acting against each other. From a clinical perspective, it's also a safety measure, and it's important to have in consideration that antagonism was not observed between these β-lactams,” Alexander said.

References
1. Enterococcus faecalis. Wikipedia. Accessed August 13, 2025.
https://en.wikipedia.org/wiki/Enterococcus_faecalis
2. What is the best synergistic combination against Enterococcus faecalis? in-vitro synergy activity of ampicillin in combination with cephalosporins and carbapenems for determining synergy, addition, and antagonism. Presented at: American Society for Microbiology Microbe 2025; June 19-23, 2025; Los Angeles, CA.