The combination of ceftaroline plus daptomycin allows for therapeutic de-escalation and daptomycin sparing against MRSA

Objectives: We previously demonstrated that ceftaroline enhances daptomycin against MRSA in vitro. However, prolonged combination therapy is clinically undesirable and possibly unnecessary. The purpose of this study was to determine if this combination could be de-escalated to a single agent without compromising efficacy. Methods: We investigated the following simulated regimens against two clinical, daptomycin-non-susceptible MRSA isolates in an in vitro pharmacokinetic/pharmacodynamic hollow-fibre model over 192 h: 600 mg of ceftaroline every 12 h (fC(max) 17.0 mg/L, t(1/2) 2.66 h); 10 mg/kg/day daptomycin (fC(max) 11.3 mg/L, t(1/2) 8 h); 6 mg/kg/day daptomycin (fC(max) 7.5 mg/L, t(1/2) 8 h); ceftaroline+daptomycin; and ceftaroline+daptomycin de-escalated to ceftaroline, daptomycin or drug-free simulations. Results: Daptomycin and ceftaroline MICs were 2 and 2 and 0.5 and 1 mg/L for strains R6063 and R5563, respectively. Ceftaroline+daptomycin (6 or 10 mg/kg/day) achieved a>5 log(10) cfu/mL reduction within 96 h against both strains. Bacterial counts remained,1.5 log(10) cfu/mL from 96 to 192 h regardless of de-escalation to either agent. There were no significant differences between combination or de-escalation regimens for either organism at either daptomycin dose. All combination/de-escalation to monotherapy regimens resulted in significantly improved activity compared with drug-free control, ceftaroline or daptomycin monotherapy (P<0.01). Conclusions: These findings confirm that ceftaroline+daptomycin is a potent combination against MRSA. The high degree of bactericidal activity observed with this combination appears sufficiently robust to allow for de-escalation to a single agent without bacterial regrowth. The equivalent activity observed with ceftaroline+daptomycin (6 and 10 mg/kg/day) suggests this combination could also be daptomycin sparing. Further research is warranted to optimize dose and de-escalation timing.