Adjunctive β-lactams in combination therapy for enterococcal bacteremia and endovascular infections: A narrative review

Enterococcal bacteremia and endovascular infections remain difficult to treat because of intrinsic antimicrobial tolerance, increasing resistance, and frequent involvement of high-inoculum or deep-seated infection. While β-lactams generally demonstrate limited bacterial killing activity against enterococci when used alone, accumulating experimental and clinical data suggest that selected β-lactams may enhance the activity of companion agents, particularly daptomycin. This narrative review summarizes the mechanistic rationale, preclinical evidence, and available clinical data supporting adjunctive β-lactams for enterococcal bacteremia and endovascular infections. The strongest clinical evidence supports ampicillin plus ceftriaxone for Enterococcus faecalis infective endocarditis, whereas emerging data suggest that selected β-lactams may potentiate high-dose daptomycin against vancomycin-resistant Enterococcus faecium . Proposed mechanisms include complementary penicillin-binding protein inhibition, alterations in cell envelope physiology, increased antimicrobial binding, and suppression of resistance emergence. However, available clinical data are derived largely from retrospective studies and remain heterogenous with respect to patient populations, infectious syndromes, β-lactam selection, dosing strategies, and treatment duration. Current evidence favors a phenotype-directed approach rather than routine combination therapy for all enterococcal bloodstream infections. Adjunctive β-lactams appear most justifiable in patients with persistent bacteremia, endovascular infection, high-inoculum disease, elevated daptomycin minimum inhibitory concentrations, prosthetic material, or other features associated with microbiologic failure or relapse, whereas uncomplicated bacteremia may derive limited benefit. Important questions remain regarding optimal patient selection, β-lactam choice, and duration of therapy. Given the practical and financial barriers to conducting randomized trials in this population, mechanistic, translational, and observational studies will likely remain the foundation of real-world clinical decision-making.