Evaluation of ceftaroline activity versus daptomycin (DAP) against DAP-nonsusceptible methicillin-resistant Staphylococcus aureus strains in an in vitro pharmacokinetic/pharmacodynamic model

Abstract

The objective of this study was to investigate the potential role of ceftaroline, a new broad-spectrum cephalosporin, as a therapeutic option for the treatment of daptomycin-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) infections. Four clinical DNS MRSA strains, R5717, R5563, R5996 (heteroresistant vancomycin-intermediate S. aureus) and R5995 (vancomycin-intermediate S. aureus) were evaluated in a two-compartment hollow-fiber in vitro pharmacokinetic/pharmacodynamic model at a starting inoculum of 10(7) CFU/ml for 96 h. Simulated regimens were ceftaroline at 600 mg every 12 h (q12h) (maximum free-drug concentration [fC(max)], 15.2 μg/ml; serum half-life [t(1/2)], 2.3 h), daptomycin at 6 mg/kg q24h (fC(max), 7.9 μg/ml; t(1/2), 8 h), and daptomycin at 10 mg/kg q24h (fC(max), 15.2 μg/ml; t(1/2), 8 h). Differences in CFU/ml between 24 and 96 h were evaluated by analysis of variance with Tukey's post-hoc test. Bactericidal activity was defined as a ≥3-log(10) CFU/ml decrease in the colony count from the initial inoculum. The ceftaroline MIC values were 0.25, 0.5, 0.5, and 0.5 μg/ml, and the daptomycin MIC values were 2, 2, 4, and 4 μg/ml for R5717, R5563, R5996, and R5995, respectively. Ceftaroline displayed sustained bactericidal activity against 3 of the 4 strains at 96 h (R5717, -3.1 log(10) CFU/ml; R5563, -2.5 log(10) CFU/ml; R5996, -5.77 log(10) CFU/ml; R5995, -6.38 log(10) CFU/ml). Regrowth occurred during the daptomycin at 6-mg/kg q24h regimen (4 strains) and the daptomycin at 10-mg/kg q24h regimen (3 strains). At 96 h, ceftaroline was significantly more active, resulting in CFU/ml counts lower than those obtained with daptomycin at 6 mg/kg q24h (4 strains, P ≤ 0.008) and daptomycin at 10 mg/kg q24 h (3 strains, P ≤ 0.001). Isolates with increased MIC values for daptomycin (all 4 strains) but not for ceftaroline were recovered. Ceftaroline was effective against the 4 isolates tested and may provide a clinical option for the treatment of DNS MRSA infections.

Fig. 1.

Activities of CPT, DAP6, and DAP10 against R5717 (A), R5563 (B), R5995 (VISA) (C), and R5996 (hVISA) (D). Closed circles, growth control; open circles, CPT at 600 mg q12h; closed triangles, DAP6; open triangles, DAP10. Error bars are standard deviations of 2 independent experiments.