Time to Reappraise the Antibiotic Treatment for Methicillin-Susceptible Staphylococcus aureus Infective Endocarditis: Data From the Experimental Model.

Abstract

BACKGROUND: Traditional treatment of methicillin-susceptible Staphylococcus aureus (MSSA) native valve endocarditis is based on cloxacillin/cefazolin monotherapy. Antibiotics with high activity against MSSA, such as ceftaroline and daptomycin, have been marketed for years, but there are no clinical trials evaluating them as monotherapy or combination therapy in patients with MSSA endocarditis. The objective of this study was to compare the efficacy of cloxacillin, ceftaroline, and daptomycin monotherapies and daptomycin combinations with β-lactams in a rabbit model of MSSA endocarditis. METHODS: Endocarditis was induced in rabbits with 2 strains of MSSA. After 24 hours of infection, they received human-like doses of cloxacillin, ceftaroline, or daptomycin or combinations of daptomycin plus either cloxacillin or ceftaroline. Isolates recovered from vegetation, spleen, and kidney were retested for daptomycin nonsusceptibility (DNS) posttreatment. RESULTS: MSSA vancomycin minimum inhibitory concentration did not influence the efficacy of any antibiotic treatment. Cloxacillin, ceftaroline, and daptomycin had similar activity (25%-50%) in sterilizing vegetations. However, 13% of rabbits treated with daptomycin developed DNS. The addition of daptomycin to cloxacillin or ceftaroline was synergistic and bactericidal, showing significantly more activity and higher rates of sterile vegetations (≥90%) than any monotherapy. Combinations also showed better activity in spleens and kidneys as compared with daptomycin monotherapy and prevented the development of DNS in all tissues. There were no differences between the daptomycin combinations. CONCLUSIONS: In the MSSA experimental endocarditis model, daptomycin combinations with β-lactams had significantly better activity than any of the monotherapies in sterilizing valve vegetations and preventing DNS development. These findings support their use in clinical practice and to perform clinical trials.