A combination of ceftaroline and daptomycin has synergistic and bactericidal activityin vitroagainst daptomycin nonsusceptible methicillin-resistantStaphylococcus aureus(MRSA)

Abstract

There is an urgent need to optimize therapeutic options in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia who have failed conventional therapy. Two clinical isolates were obtained from a 68-year-old male with persistent MRSA bacteremia before and after the development of daptomycin nonsusceptibility. The pharmacodynamic activity of monotherapies and combinations of ceftaroline, daptomycin, cefoxitin, nafcillin and vancomycin were evaluated in time-kill experiments versus 10 CFU/mL of the pre- and post-daptomycin nonsusceptible MRSA isolates. Cefoxitin, nafcillin and vancomycin alone or in combination with ceftaroline failed to generate prolonged bactericidal activity against the post-daptomycin nonsusceptible isolate whereas a ceftaroline-daptomycin combination resulted in 6, 24 and 48 h log(CFU/mL) reductions of 3.90, 4.40 and 6.32. Population analysis profiles revealed a daptomycin heteroresistant subpopulation of the pre-daptomycin nonsusceptible MRSA isolate that expanded by >10,000× on daptomycin agar containing 2-16 mg/L in the post-daptomycin nonsusceptible isolate. Daptomycin and ceftaroline combinations may be promising against persistent MRSA bacteremia.

Adjunctive ceftaroline in combination with daptomycin or vancomycin for complicated methicillin-resistant Staphylococcus aureus bacteremia after monotherapy failure

“…33,34 Likely the most compelling evidence for synergism lies with those reports describing clinical success and accompanying in vitro evidence of improvement or restoration of drug susceptibility in the presence of CPT. 21,22,29…”

“…Clinical success has been reported with CPT in combination with both DAP and VAN for treating MRSA-B; however, no comparative studies are available or describe a single center's experience with both regimens. [12][13][14][18][19][20][21][22] We are interested in the potential for these regimens to improve clinical outcomes in patients with MRSA-B. Here, we report on our singlecenter experience using DAP/CPT or VAN/CPT as treatment options for complicated MRSA bacteremia following monotherapy failure.…”

Comparing the Outcomes of Ceftaroline Plus Vancomycin or Daptomycin Combination Therapy Versus Monotherapy in Adults with Complicated and Prolonged Methicillin-Resistant Staphylococcus Aureus Bacteremia Initially Treated with Supplemental Ceftaroline

“…Ceftaroline's value in treating MRSA bacteremia secondary to non-ABSSSI causes such as infective endocarditis and osteomyelitis [8,9] led to its investigational use as a salvage measure for vancomycin-or daptomycin-refractory MRSA bacteremia [9,10]. Findings of bacteremia resolution plus in vitro evidence of antibiotic synergy [11,12] motivated others to follow suit. Nowadays, it is common practice to add ceftaroline to patients with persistent bacteremia despite vancomycin or daptomycin.…”

Daptomycin and combination daptomycin-ceftaroline as salvage therapy for persistent methicillin-resistant Staphylococcus aureus bacteremia

“…We read with interest a recent report in the present journal describing synergistic bactericidal activity in vitro against a daptomycin nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA) isolate [1]. A ceftaroline-daptomycin combination resulted in a reduction of 6.15 log10 (CFU/mL) at 48 h. Beta-lactams with affinity for penicillin-binding protein (PBP) 1 enhance the antimicrobial activity of daptomycin; this effect appears to be mediated by improved daptomycin binding to the bacterial cell membrane [2].…”