RESUMEN
Prosthetic heart valve sewing rings were impregnated with gentamicin crobefat (EMD 46217), a poorly soluble gentamicin salt, gentamicin sulfate, and clindamycin palmitate to prevent early prosthetic endocarditis. MICs and MBCs of gentamicin and/or clindamycin were tested against several pathogens of early prosthetic endocarditis. The combination of gentamicin and clindamycin was found to be effective against most relevant bacterial pathogens. With an in vitro pharmacokinetic model, the antibacterial activity of gentamicin and clindamycin was tested against Staphylococcus aureus and Escherichia coli. High gentamicin levels over the first 24 h were required for a strong reduction of bacterial counts of both strains. Equal amounts of gentamicin and clindamycin sustained the antibacterial effect and prevented regrowth. The most effective release curves of gentamicin and clindamycin found with an in vitro model were used for monitoring release profiles of these antibiotics from impregnated sewing rings by investigating combinations of gentamicin sulfate, gentamicin crobefat, and clindamycin palmitate. Sewing rings impregnated with 4 mg of gentamicin sulfate, 14 mg of gentamicin crobefat, and 20 mg of clindamycin palmitate gave an initial gentamicin burst and afterwards yielded a lower sustained release of gentamicin and clindamycin palmitate. These in vitro release kinetics were confirmed in vivo by pharmacokinetic analysis after intramuscular implantation of impregnated sewing ring segments. Gentamicin and active clindamycin palmitate metabolites were obtained at the implantation site for at least 2 weeks in concentrations of 3 and 5 micrograms per g of muscle, respectively. The investigated method of impregnation holds promise for revision implants after prosthetic valve endocarditis. It may also serve as a prophylactic tool for routine use against this disease.
