Jörg Michael Schierholz

Efficacy of silver-coated medical devices.

Silver coating of medical devices is believed to prevent device-associated infection. Several in-vitro and in-vivo studies, as well as clinical observations on silver-nylon, silver-intramedullary pins, silver oxide Foley catheters and silver-coated vascular prostheses have been performed during the past 30 years. Nevertheless, randomized clinical studies showing efficacy of such coated medical devices in high-risk patient populations are rare, have dealt with very small numbers of patients or are controversial. Physico-chemical, pharmacological and microbiological data explaining the antimicrobial efficacy of silver in prophylaxis of implants are presented here, as well as the scientific background for the established clinical benefits of silver-preparations in burns.

Controlled release of antibiotics from biomedical polyurethanes: morphological and structural features

Polymer-associated infections are of increasing importance. Antistaphylococcal antimicrobial substances (ciprofloxacin, gentamycin, fosfomycin, flucloxacillin) were incorporated into polyurethanes by the solvent casting technique. Drug release rates, bacterial colonization and morphological features were evaluated to predict and understand the antimicrobial activity of these delivery systems. Drug release characteristics were investigated by standard bioassay and high-performance liquid chromatography (HPLC), and the physico-chemical mechanisms of the delivery were discussed. Ciprofloxacin hydrochloride showed a fast initial release rate, whereas gentamicin-base was characterized by a more continuous release type of behaviour. Bacterial colonization to the antibiotic-loaded polyurethanes was inhibited effectively by preparations showing a slower but more sustained antimicrobial delivery. Polyurethane-antibiotic combinations were most homogeneous for gentamicin-base and flucloxacillin as shown by scanning electron microscopy (SEM). In polymers loaded with fosfomycin and ciprofloxacin a granular structure of the crystallized drug embedded in the polyurethane matrix could be demonstrated. Physico-chemical similarity of the polymeric material and the antibiotics is important for the homogeneity of polymer-antibiotic combinations. High homogeneity is required for a sustained and prolonged release over time and effective inhibition of bacterial colonization.

IN-VITRO EFFICACY OF AN ANTIBIOTIC RELEASING SILICONE VENTRICLE CATHETER TO PREVENT SHUNT INFECTION

Infection due to implanted polymeric devices is a major problem in modern medicine. Microbial colonization of implants in neurosurgery, e.g. cerebrospinal fluid (CSF) shunts is the main reason for their failure, and often results in the consequent removal of the infected implants. In this paper we report on new approaches in the prevention of bacterial infections by incorporation of an antibiotic (rifampicin) into the polymer devices (silicone). Drug release characteristics are investigated, and the physico-chemical mechanism of the delivery is discussed. Measurements of killing kinetics and the bacterial adhesion to the antibiotic-loaded silicone in a static adhesion assay reveal that only the liberation of high antibiotic doses over a period of weeks can prevent the bacterial colonization of the polymeric surface.

Treatment of staphylococcal implant infection with rifampicin-ciprofloxacin in stable implants

Abstract Infection following total joint replacement remains a problem that has not been solved so far. The treatment options include removal of the implant and a delayed reconstruction or a direct exchange operation. Among patients with stable implants and short duration of infection as well as in patients who for certain reasons are inoperable, antibiotic therapy with a combination of rifampicin-ciprofloxacin may be a reasonable treatment option for curing staphyloccocal infection without removal of the implant. A case study of a Staphylococcus epidermidis (coagulase-negative) infection following delayed revision total knee replacement after septic loosening of a knee arthroplasty and its successful conservative treatment with rifampicin-ciprofloxacin is described. Alternative rifampicin combinations are discussed with respect to recently developed pharmacodynamical and pharmacokinetical findings of biofilm active drugs.

Antimicrobial substances and effects on sessile bacteria.

Biofilms occur in natural aquatic ecosystems and on surfaces of biomaterials. They are generally associated with clinical infections predominantly of prosthetic hip joints, heart valves and catheters. Sessile microorganisms may be intimately associated with each other and to solid substratum through binding to and inclusion into exopolymer matrices on biofilms. The establishment of functional colonies within the exopolymeric matrices generate physico-chemical gradients within biofilms, that modify the metabolism and cell-wall properties of the microorganism. A consequence of biofilm growth is an enhanced microbial resistance to chemical antimicrobial agents and antibiotics. Investigations on the antimicrobial efficacy of antibiotics, antiseptics and antimicrobial heavy ions, however, gave controversial results. No single antimicrobial substance has been developed for the efficient eradication of adherent bacteria. This review elucidates the mechanisms of microbial resistance in biofilms and strategies for the prevention of biofilm development. Pharmacokinetical and pharmacodynamical issues for the screening of biofilm-active drugs are presented. Combinations of antistaphylococcal antibiotics with rifampin may be advantageous for preventing and curing biomaterial infections.

Physico-chemical properties of a rifampicin-releasing polydimethyl-siloxane shunt

Infection of implanted polymeric devices is a major problem in modern medicine. Silicone shunts were modified in order to prevent microbial colonization by incorporating rifampicin. The release mechanism and the altered properties of the silicone were studied. Release rates of rifampicin out of the polymeric shunt materia were measured in vitro for up to 60 d. For high velocity of rifampicin in the polymeric matrix and long-lasting controlled release rates, high compatibility of polymer and drug was required. Compatibility and therefore miscibility of drug and polymer were estimated by reduced solubility and cohesion energy densities (Hansen parameter, solubility parameter delta). Mechanical properties of the polymer were influenced by incorporation of small drug amounts, characterized by stress-strain curves. Differential scanning calorimetry (DSC) measurements suggested thermodynamically controlled interaction of the macromolecules with the incorporated substance. The physico-chemical state of the drug in the internal phase and the surface of the polymer was studied by scanning electron micrography (SEM), showing homogeneous molecular dispersion of the drug in the polymeric material as well as crystalline structures on the surface.

Development of a New CSF-shunt with Sustained Release of an Antimicrobial Broad-spectrum Combination

The use of Cerebro-Spinal-Fluid-shunts (CSF-shunts) is often associated with infectious complications, because bacteria tend to colonize plastic material. The use of plastic materials with antibacterial activity may reduce catheter related bacterial colonization. A novel CSF-shunt impregnated with a broad-spectrum antimicrobial combination was designed in order to meet two requirements; lack of toxicity and persistence of antimicrobial efficacy. Incorporation of three antibiotics up to 10% (wt/wt) into the shunt material (polydimethyl-siloxane) was required for sustained release for more than 100 days, measured by HPLC. The combination of antimicrobials showed additive and synergistical effects as measured by the checker-board and time kill technique. These antimicrobial combinations prevented mutations in resistance inducing experiments with several S. epidermidis and S. aureus strains. Using large challenge doses of S. aureus in a catheter colonization model, antimicrobially modified catheters were protected against bacterial colonization for more than 14 days. Using a C3a-des-Arg-ELISA-test and a CH50-hemolysis test the modified catheter was as biocompatible as the unmodified shunt material. These encouraging results indicate that such antibiotic-bonded catheters substantially reduce the incidence and magnitude of catheter-related bacterial colonization and may substantially reduce CSF-shunt infection.

Anti-infective catheters : A difficult search for effective slow delivery systems

Nosocomial infection are estimated to involve more than 2 million patients annually and in 1992 cost more than

Drug Delivery Concepts for the Efficacious Prevention of Foreign-Body Infections*

4,5 billion in the USA (1). The surfaces of indwelling medical devices are an excellent platform for the formation of life-threatening infections. Although aseptic techniques can reduce the incidence of these infections, a significant risk remains. The coupling or incorporation of antimicrobial substances to or into catheter materials may be a suitable way to prevent the development of catheter associated infections as suggested by in vitro and in vivo studies. Various surface treatments are emerging as important. Early efforts that concentrated on adsorption of antibiotics to device surfaces achieved limited results as shown in several clinical studies. The promising approach features the incorporation of antimicrobial drugs into the polymer matrices that entrap but do not bind the drugs, allowing for extended release. Incorporation of antimicrobials in the bulk material that constitutes a device can be effective as shown in several in vitro and in vivo studies. In future, modification of both short-term and long term catheters by biofilm-active antimicrobials creating slow delivery systems may provide an effective method to protect patients from nosocomial infection. Antimikrobielle Kathetermaterialien: Schwierige Suche nach wirksamen Wirkstoffliberations-Systemen In den USA werden jedes Jahr mehr als zwei Millionen nosokomiale Infektionen gezahlt mit geschatzten Kosten von mehr als 4,5 Milliarden

Killing effects of antibiotics and two-fold antimicrobial combinations on proliferating and non growing staphylococci

(1). Die Oberflachen von Implantatmaterialien sowie invasiver Medizinprodukte bieten ideale Wachstums- und Ausbreitungsbedingungen fur nosokomiale Keime. Unter strikter Beachtung steriler Kautelen lasst sich die Haufigkeit Implantat-assoziierter Infektionen reduzieren; trotzdem verbleibt eine „physiologische”, kaum vermeidbare Infekthaufigkeit. Die Kopplung antimikrobiell aktiver Substanzen an oder in Implantatmaterialien vermag in naher Zukunft die Haufigkeit dieser Infektionen reduzieren, worauf inzwischen in vitro und auch klinische Studien hinweisen. Die in der Vergangenheit haufig beschrittene oberflachliche Implantatbeschichtung mit antimikrobiellen Substanzen konnte sich aufgrund widerspruchlicher klinischer Resultate nicht durchsetzen. Physikalisch in der Implantatmatrix gebundene Biofilm-aktive Wirkstoffe konnen mittels Diffusion uber einen langeren Zeitraum freigesetzt werden und eroffnen somit ein effizientes pharmakologisches Wirkprinzip zur Pravention dieser Infektionen.