This study conducted for 15 months, was carried out in 34 patients with beta-lactam allergy scheduled for open heart surgery. In the study, pefloxacin was given orally an hour before the induction of anaesthesia and then as a short infusion following induction. When the bypass was stopped, pefloxacin (400 mg) and fosfomycin (60 mg.kg-1) were given in association by two separate slow intravenous infusions just before sternal closure and repeated in intensive care unit postoperatively. The antibiotic kinetics was observed in blood and cellular concentrations (atria, sternum and mediastinal part of pleura). The antibiotic level analysis showed a good diffusion during the surgical procedure, particularly during the bypass. The pefloxacin given orally was found to achieve satisfactory plasma levels of 5.4 to 6.9 mg.l-1 during sternotomy and always higher than 3 mg.l-1 during bypass. At the sternal closure, the residual plasma level was about 2.8 mg.l-1 before the reinfusion. The kinetic evaluation of fosfomycin has also shown same effective levels. Hence, the clinical potency of these antibiotics was confirmed as predicted by their excellent tissue diffusion. Thus, clinical evaluation was in favour of this antibiotic-association in most cases, except the two following ones. The first case had a lethal bronchiolar and lung reinfection with Pseudomonas aeruginosa and Candida albicans germs which appeared at the 6th postoperative day. The second patient is a case of antibiotic prophylaxis failure. He had developed an acute suppurating mediastinal infection at the seventh postoperative day with a methicillin resistant Staphylococcus aureus which had become pefloxacin fosfomycin resistant. However, the evolution was ultimately good after surgical disinfection of sternotomy and 30 days of drainage and irrigation with antiseptic solution associated with well adapted antibiotic treatment: vancomycin, pristinamycin and rifamycin. In fact, the choice of pefloxacin and fosfomycin for prophylaxis against staphylococcus in cardiac surgery is the right choice for patients having beta-lactam allergy. Their spectral activity and pharmacokinetics give us satisfactory results. But it is not the absolute solution as the bacteria responsible for nosocomial infection (hospital borne infection) may be found resistant to this association.