fosfomycin and Mediastinitis

A prospective clinical study was carried out to assess the adequacy of perioperative antibiotic prophylaxis using fosfomycin in patients undergoing open-heart surgery for valve diseases for the prevention of early postoperative endocarditis, as well as for serious mediastinal infections that are caused mostly by multiresistant staphylococci and Gram-negative bacteria. Perioperative pharmacokinetics and tissue penetration were determined within the harvested heart valves and subcutaneous tissue. Reliable bactericidal serum levels were established at the first measurement 10 min after the end of intravenous infusion (203.7 +/- 44.7 micrograms/ml) and were maintained during surgery for at least 120 min (124.6 +/- 58.4 micrograms/ml), even in cases of prolonged extracorporeal circulation. Cardiopulmonary bypass did not alter the serum elimination of fosfomycin in comparison with patients not undergoing extracorporeal circulation. Peak tissue concentrations were achieved in both aortic and mitral valves after 30 min, ranging between 27.1 and 76.9 micrograms/g for aortic valves and 39.6-69.4 micrograms/g for mitral valves, depending on the degree of valvular degeneration. MIC values of 16 micrograms/g were maintained in both valves for at least up to 60 min. There was no evidence of renal impairment, adverse reactions or infections during the postoperative course or thereafter for a period of 3 months. It is concluded that perioperative intravenous antibiotic prophylaxis using fosfomycin (5 g t.i.d. in adults), beginning with induction of anesthesia and continued for 48 h postoperatively, provides rapid, reliable bactericidal serum levels and valvular tissue concentrations that will inhibit most Gram-positive and Gram-negative organisms that cause bacterial endocarditis and other serious infections following cardiac surgery.

Topics: Aged; Aortic Valve; Endocarditis, Bacterial; Extracorporeal Circulation; Female; Fosfomycin; Heart Valve Diseases; Heart Valve Prosthesis; Humans; Male; Mediastinitis; Metabolic Clearance Rate; Middle Aged; Mitral Valve; Prospective Studies; Surgical Wound Infection

Fosfomycin is a molecule that inhibits the early stage of peptidoglycan synthesis and shows a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria. Using the Killing-curve method, we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL, that is easily achievable in serum at standard dosing regimens, against seven methicillin-resistant Staphylococcus aureus strains, isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy. MICs of vancomycin ranged from 1 to 4 microg/mL, MICs of teicoplanin from 2 to 8 microg/mL; MICs of fosfomycin were 8 microg/mL for two strains and >128 microg/mL for the remaining strains. The seven strains proved tolerant when tested for vancomycin and teicoplanin used alone at 2x MIC concentration. Fosfomycin was bactericidal (reduction of 2 log of the inoculum) only against the two susceptible strains. In all cases both vancomycin and teicoplanin in combination with fosfomycin developed bactericidal synergism already at a concentration of 1x MIC. If these results are confirmed by in vivo experiments, the combination of fosfomycin with glycopeptides might be useful for treating device-associated infections, and in preventing the phenomenon of increasing MICs for glycopeptides.

Topics: Anti-Bacterial Agents; Bacteremia; Blood Vessel Prosthesis; Catheterization; Device Removal; Drainage; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Synergism; Electrophoresis, Gel, Pulsed-Field; Equipment Contamination; Fosfomycin; Glycopeptides; Humans; Mediastinitis; Methicillin Resistance; Pacemaker, Artificial; Postoperative Complications; Prosthesis-Related Infections; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin; Vancomycin