To minimize the incidence of postoperative infections in patients undergoing open-heart surgery, antibiotics should maintain tissue concentrations greater than the minimal inhibitory concentration (MIC) for potential pathogens (eg, Staphylococcus) for the duration of the operation. The ability of cefonicid, a new β-lactamase-resistant parenteral cephalosporin, to attain plasma and myocardial levels greater than the MIC (4.8 to 5.0 μg/mL) for penicillin-resistant Staphylococci was assessed in 13 patients. Six patients were administered 1 g and seven patients were administered 2 g of cefonicid IM one hour prior to surgery. In all patients the plasma concentrations of the drug were determined at the start of surgery, 15 minutes after the patient was placed on cardiopulmonary bypass (CPB), and at the completion of CPB. In addition, the concentration of cefonicid was determined in a right atrial biopsy. It was found that both 1 g and 2 g of cefonicid administered one hour prior to surgery resulted in plasma and myocardial levels greater than the MIC for the organisms most frequently implicated in postoperative infections.