Abstract
Ceftaroline fosamil, a fifth-generation cephalosporin antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA), is currently approved for the treatment of pneumonia and complicated skin and soft tissue infections. However, pharmacokinetics data on free lung tissue concentrations in critical patient populations are lacking. The aim of this study was to evaluate the pharmacokinetics of the high-dose regimen of ceftaroline in plasma and lung tissue in cardiac surgery patients during intermittent and continuous administration. Nine patients undergoing elective cardiac surgery on cardiopulmonary bypass were included in this study and randomly assigned to intermittent or continuous administration. Eighteen hundred milligrams of ceftaroline fosamil was administered intravenously as either 600 mg over 2 h every 8 h (q8h) (intermittent group) or 600 mg over 2 h (loading dose) plus 1,200 mg over 22 h (continuous group). Interstitial lung tissue concentrations were measured by in vivo microdialysis. Relevant pharmacokinetics parameters were calculated for each group. Plasma exposure levels during intermittent and continuous administration were comparable to those of previously published studies and did not differ significantly between the two groups. In vivo microdialysis demonstrated reliable and adequate penetration of ceftaroline into lung tissue during intermittent and continuous administration. The steady-state area under the concentration-time curve from 0 to 8 h (AUC(ss 0-8)) and the ratio of AUC(SS 0-8) in lung tissue and AUC in plasma (AUC(lung/plasma)) were descriptively higher in the continuous group. Continuous administration of ceftaroline fosamil achieved a significantly higher proportion of time for which the free drug concentration remained above 4 times the minimal inhibitory concentration (MIC) during the dosing interval (% fT(>4xMIC)) than intermittent administration for pathogens with a MIC of 1 mg/liter. Ceftaroline showed adequate penetration into interstitial lung tissue of critically ill patients undergoing major cardiothoracic surgery, supporting its use for pneumonia caused by susceptible pathogens.