Novel fatty acid gentamicin salts as slow-release drug carrier systems for anti-infective protection of vascular biomaterials.

Infections of vascular prostheses are still a major risk in surgery. The current work presents an in vitro evaluation of novel slow release antibiotic coatings based on new gentamicin fatty acid salts for polytetrafluoroethylene grafts. These grafts were coated with gentamicin sodium dodecyl sulfate, gentamicin laurate and gentamicin palmitate. Drug release kinetics, anti-infective characteristics, biocompatibility and haemocompatibility of developed coatings were compared to commercially available gelatin sealed PTFE grafts (SEALPTFE™) and knitted silver coated Dacron(®) grafts (InterGard(®)). Each gentamicin fatty acid coating showed a continuous drug release in the first eight hours followed by a low continuous release. Grafts coated with gentamicin fatty acids reduced bacterial growth even beyond pathologically relevant high concentrations. Cytotoxicity levels depending on drug formulation bringing up gentamicin palmitate as the most promising biocompatible coating. Thrombelastography studies, ELISA assays and an amidolytic substrate assay confirmed haemocompatibility of developed gentamicin fatty acid coatings comparable to commercially available grafts.

Magnetic Drug Targeting as New Therapeutic Option for the Treatment of Biomaterial Infections.

Implant-associated infections are a challenging problem in surgery. Bacteria in biofilms are difficult to treat as they are less susceptible to antibiotics or antiseptics which require high drug concentrations at the site of infection. We present a novel strategy to concentrate high antibiotic doses systemically at the target site using newly developed antibiotic-functionalized nanoparticles directed by a magnetic drug-targeting system. The important and effective antibiotic gentamicin served as antimicrobial substance and was ionically or covalently attached to magnetic nanoparticles. Subsequently, the particles were characterized thoroughly. Anti-infective properties with regard to Staphylococcus aureus and the degree of cytotoxicity concerning human umbilical vein endothelial cells were determined. The enrichment of the magnetic nanoparticles at the surface of model tubes in circulatory experiments was investigated. We describe a promising technique for the loading of magnetic nanoparticles to treat systemic infections. Gentamicin-coated magnetic nanoparticles reduced bacterial growth even beyond pathologically relevant concentrations within 24 h. Excellent concentration independent biocompatibility was found for the nanoparticles themselves and we demonstrate that the magnetic nanoparticles can be navigated and concentrated on surfaces of model implants using a permanent magnetic field.

Augmentation of antibiotic activity by low-frequency electric and electromagnetic fields examining Staphylococcus aureus in broth media.

Systemic treatment of biomaterial-associated bacterial infections with high doses of antibiotics is an established therapeutic concept. The purpose of this in vitro study was to determine the influence of magnetic, electromagnetic, and electric fields on gentamicin-based, antibiotic therapy. It has been previously reported that these fields are successful in the treatment of bone healing and reducing osteitis in infected tibia-pseudarthroses. Four separate experimental setups were used to expose bacterial cultures of Staphylococcus aureus both in Mueller-Hinton broth (MHB) and on Mueller-Hinton agar (MHA), in the presence of gentamicin, to (1) a low-frequency magnetic field (MF) 20 Hz, 5 mT; (2) a low-frequency MF combined with an additional alternating electric field (MF + EF) 20 Hz, 5 mT, 470 mV/cm; (3) a sinusoidal alternating electric field (EF AC) 20 Hz, 470 mV/cm; and (4) a direct current electric field (EF DC) 588 mV/cm. No significant difference between samples and controls was detected on MHA. However, in MHB each of the four fields applied showed a significant growth reduction of planktonically grown Staphylococcus aureus in the presence of gentamicin between 32% and 91% within 24 h of the experiment. The best results were obtained by a direct current EF, decreasing colony-forming units (CFU)/ml more than 91%. The application of electromagnetic fields in the area of implant and bone infections could offer new perspectives in antibiotic treatment and antimicrobial chemotherapy.

New anti-infective coatings of surgical sutures based on a combination of antiseptics and fatty acids.

Wound infection is a complication feared in surgery. The aim of this study was to develop new anti-infective coatings of surgical sutures and to compare the anti-microbial effectiveness and biocompatibility to the well-established Vicryl Plus. Synthetic absorbable PGA surgical sutures were coated with three different chlorhexidine concentrations and two different octenidine concentrations in combination with palmitic acid and lauric acid. Drug-release kinetics lasting 96 h were studied in phosphate-buffered saline at 37 degrees C. Anti-infective characteristics were determined by measuring the change in optical density of Staphylococcus aureus suspensions charged with coated sutures over time. Microorganisms adsorbed at the surface of coated sutures were assessed on blood agar plates and coated sutures eluted for 24 h were placed on bacterial lawns cultured on Mueller-Hinton plates to prove retained anti-microbial potency. A cell proliferation assay was performed to assess the degree of cytotoxicity. Anti-infective characteristics and biocompatibility were compared to Vicryl Plus. A coating technology for slow-release drug-delivery systems on surgical sutures could be developed. All coatings showed a continuous drug release within 96 h. Individual chlorhexidine and octenidine coated sutures showed superior anti-infective characteristics but inferior biocompatibility in comparison to Vicryl Plus. We conclude that the developed anti-infective suture coatings consisting of lipid-based drug-delivery systems in combination with antiseptics are highly effective against bacterial colonization in vitro; however, drug doses have to be adjusted to improve biocompatibility.

New anti-infective coatings of medical implants.

Implantable devices are highly susceptible to infection and are therefore a major risk in surgery. The present work presents a novel strategy to prevent the formation of a biofilm on polytetrafluoroethylene (PTFE) grafts. PTFE grafts were coated with gentamicin and teicoplanin incorporated into different lipid-like carriers under aseptic conditions in a dipping process. Poly-d,l-lactic acid, tocopherol acetate, the diglyceride Softisan 649, and the triglyceride Dynasan 118 were used as drug carriers. The drug release kinetics, anti-infective characteristics, biocompatibility, and hemocompatibility of the coatings developed were studied. All coatings showed an initial drug burst, followed by a low continuous drug release over 96 h. The dimension of release kinetics depended on the carrier used. All coated prostheses reduced bacterial growth drastically over 24 h, even below pathologically relevant concentrations. Different cytotoxic levels could be observed, revealing tocopherol acetate as the most promising biocompatible carrier. A possible reason for the highly cytotoxic effect of Softisan 649 could be assessed by demonstrating incorporated lipids in the cell soma with Oil Red O staining. Tromboelastography studies, enzyme-linked immunosorbent assays, and an amidolytic substrate assay could confirm the hemocompatibility of individual coatings. The development of the biodegradable drug delivery systems described here and in vitro studies of those systems highlight the most important requirements for effective as well as compatible anti-infective coatings of PTFE grafts. Through continuous local release, high drug levels can be produced at only the targeted area and physiological bacterial proliferation can be completely inhibited, while biocompatibility as well as hemocompatibility can be ensured.