Influence of sterilization upon a range of properties of experimental bone cements.

Bone cement, used to fix prostheses into the bone, must be sterilized prior to implantation. Two sterilization techniques, gamma and beta radiation, were investigated, examining the influence upon molecular weight, static and dynamic mechanical characteristics and rheological properties. A number of experimental cements were studied prepared from methylmethacrylate (MMA) co-polymers, either single powders or powder blends, mixed with MMA monomer. It was found that with both gamma and beta radiation, there was a decrease in molecular weight of all powders, including a MMA/styrene co-polymer, in relation to the radiation dose. This fall in molecular weight resulted in a drop in tensile strength, Young's modulus and strain to failure of all cements tested. However, the deterioration in mechanical strength was highlighted by the dynamic testing. Fatigue lives of cements after testing in tension-tension, at 2 Hz under load control and irradiated with 25 kGy gamma radiation, displayed significant decreases. This result indicated the utmost importance of conducting such tests upon experimental bone cements prior to in vivo use. The rheological time profiles of curing cements were also found to be influenced by 25 kGy gamma radiation, with a reduction of complex viscosity after sterilization.

Prevention of graft infection by bonding of gentamycin to Dacron prostheses.

To increase the efficacy of perioperative antibiotic prophylaxis in vascular surgery an experimental study including topical application of the gentamicin derivative EMD 46/217 and fibrin sealant as antibiotic carrier to Dacron prostheses was initiated. In vitro treatment of Dacron with gentamicin and fibrin was followed by constant antibiotic release for 3 weeks. In a subsequent animal study Dacron grafts were implanted in the aorta of 10 pigs after direct contamination with Staphylococcus aureus solution. One graft was pretreated with the antibiotic/fibrin compound, a second with the antibiotic alone. Grafts 3 (no pretreatment) and 4 (fibrin alone) served as controls. After 1 week the grafts and their corresponding implantation sites were excised for measurement of antibiotic content and for culture. The antibiotic content of grafts with the antibiotic/fibrin compound was 25.0 +/- 7.2 micrograms/gm wet weight, whereas Dacron pretreated with the antibiotic alone contained no measurable drug amounts except for one specimen (0.5 microgram/gm) (antibiotic/fibrin vs antibiotic, p less than .0005). The corresponding implantation sites to antibiotic/fibrin grafts contained 1.07 +/- 0.54 microgram/gm antibiotic, whereas in only 2/10 implantation sites of antibiotic grafts low antibiotic levels were found (0.05 and 0.2 microgram/gm) (antibiotic/fibrin vs antibiotic, p less than 0.005). All control grafts and 9/10 antibiotic grafts were infected. By contrast, only five were contaminated, and 5 of 10 remained sterile after culture (antibiotic/fibrin vs antibiotic, p less than 0.05). This finding correlates with the antibiotic content in the Dacron. It is concluded that pretreatment of prosthetic Dacron grafts with the antibiotic/fibrin compound results in binding of sufficient amounts of antibiotic for at least 1 week.(ABSTRACT TRUNCATED AT 250 WORDS)

The release of gentamicin after total hip replacement using low or high viscosity bone cement. A prospective, randomized study.

Low viscosity bone cement is expected to give improved long term fixation of prosthetic components by increased intrusion into cancellous bone. Fixation is more difficult to achieve after revision for infection because of the inferior quality of the bone. We have compared the amount of gentamicin released from high viscosity and low viscosity bone cements in 41 patients undergoing total hip replacement. The concentration of gentamicin in serum and the wound secretion, and the amount recovered from the urine, was about three times higher for low viscosity cement. A possible explanation for this is an increase in surface area of the cement body because of improved intrusion of cement into bone. The improved mechanical fixation and the high concentration of gentamicin of the bone cement interface favours the use of low viscosity cement, especially in revision for deep infection.

Pretreatment of prosthetic valve sewing-ring with the antibiotic/fibrin sealant compound as a prophylactic tool against prosthetic valve endocarditis.

Prosthetic valve endocarditis (PVE) remains a dreaded complication following heart valve replacement despite perioperative antibiotic (AB) prophylaxis. In order to increase the AB concentration in the sewing ring, an experimental study including topical application of the gentamicin derivative EMD 46/217 and fibrin sealant (F) as AB-carrier was initiated. In vitro pretreatment of Dacron with the gentamicin derivative and F was followed by constant AB release for 3 weeks. In a subsequent animal study, four Dacron rings with different pretreatment were implanted in the descending aorta of 10 pigs after direct contamination with 10(8) Staphylococcus aureus solution. One ring was pretreated with the AB/F compound, a second ring with the AB alone. Ring 3 (no pretreatment) and ring 4 (F alone) served as controls. After 1 week, the sewing rings and their corresponding implantation sites were assayed for measurement of AB-content and for culture. The AB content of AB/F-rings was 24.99 +/- 7.16 micrograms/g wet weight, while rings pretreated with the AB alone contained no measurable drug amounts with the exception of one specimen (0.5 microgram/g) (AB/F vs. AB-rings: P less than 0.0005). The corresponding implantation sites to AB/F rings contained 1.07 +/- 0.54 micrograms/g AB, whereas in only 2 of 10 implantation sites of AB rings, low AB levels were found (0.05 and 0.2 micrograms/g) (AB/F vs. AB ring implantation sites: P less than 0.0005). While all control rings and 9 of 10 AB rings were infected, 5 of 10 AB/F rings remained sterile after culture (AB/F vs. AB rings: P = 0.05). This finding correlated with the AB content in the suture rings.(ABSTRACT TRUNCATED AT 250 WORDS)

Reaction of the bone structure to methotrexate-Palacos flow y. Experimental investigations in animals.

With the combined osteosynthesis of pathological fractures in association with tumors and/or metastases in mind, E. Merck (Darmstadt, FRG) developed a bone cement containing a cytostatic agent, methotrexate-Palacos flow y (MTX-Pf). The animal-experimental study presented here investigates the tolerability of MTX-Pf in the femurs of rabbits with lateral comparison. In these investigations we used both the concentration of 0.63% MTX, as is currently used in standard clinical surgery, as well as a much higher concentration of 2.5% MTX. The histological sections were investigated using microradiographic methods and provided no indication of any significant differences between the femora with the MTX-Pf implantation and those into which standard Palacos flow y had been implanted.

[Bone cement containing cytostatic drugs: new aspects in the treatment of malignant bone tumors. I. Experimental studies]. / Cytostaticahaltiger Knochenzement: Neue Aspekte in der Behandlung maligner Knochentumoren. I. Experimentelle Untersuchungen.

Radical surgery in malignant bone tumors can either be limited by anatomical structures or seems inadequate in the palliative stabilization of bone metastases. Incomplete removal of the tumor and stabilization by compound osteosynthesis or endoprosthesis contains two problems: 1) the wide spread of malignant cells by manipulation in the tumor bearing area; 2) progressive destruction of bone due to remaining tumor. To overcome these problems we developed methotrexate bone cement (MTX-Palacos) with the aim to obtain high local concentrations of methotrexate in order to destroy remaining tumor cells and avoid systemic side effects. In vitro studies showed that methotrexate is released continuously from this cement without relevant changes of its biomechanical properties. Animal studies with transplanted osteosarcomas and mamma carcinomas in mice showed a considerable decrease of tumor growth when a plug of MTX-Palacos was inserted in the center of the tumor. Histological findings showed that in the surroundings of the plug the tumor was destroyed considerably contrary to normal bone cement which had no effect on the tumor at all. The results are discussed with regard to clinical application of MTX-Palacos.

Pharmacokinetic study of gentamicin-loaded cement in total hip replacements. Comparative effects of varying dosage.

A randomised, double-blind study was performed in two groups of 15 patients undergoing total hip replacements, using antibiotic-loaded acrylic cement containing 0.5 g and 1.0 g gentamicin base respectively per 40 g pack of powdered polymer. Postoperatively, the gentamicin levels in the blood, in the urine and in the wound drainage fluid were measured. In both groups of patients, the serum gentamicin concentrations were low whereas the wound drainage fluid contained highly effective antibacterial concentrations. Serum, urine and wound secretion levels showed approximately two-fold higher concentrations in the group of patients receiving the higher gentamicin load.

Antibiotics and bone cements. Experimental and clinical long-term observations.

Comparing several antibiotics and different bone cements, the mixture of Palacos R (polymethylmethacrylate, PMMA) with gentamicin proved to be the most suitable one as far as a high and sustained release of the antibiotic from the artificial resin is concerned. A continuous leaching of gentamicin was observed for more than 5 years. Gentamicin proved to be stable in Palacos R for the whole period of time. The release of 12 antibiotics from Palacos R was evaluated in vitro. Four other bone cements were included in this study as well, in order to evaluate the leaching of gentamicin from these materials. The combination Gentamicin-Palacos R (GP) showed a 2--3 fold higher and much more prolonged release than did the other mixtures. From this investigation, which also included studies of commercially available antibiotic bone cement mixtures, it is quite obvious that there exist distinct differences in the various bone cements as well as in the various antibiotics as regards their qualification for use in alloarthroplasty. Pharmacokinetic studies in patients after implantation of GP showed low gentamicin concentrations in serum (on average 1.8 microgram/ml) and urine. However, in wound exudate, derived directly from the vicinity of the implanted cement, gentamicin concentrations up to 150 micrograms/ml were observed. Also in tissue samples from the vicinity of the implant, high concentrations were measurable for a long period of time (up to 5 1/2 years).

[Experimental and pharmacokinetic studies with gentamicin PMMA beads (author's transl)]. / Experimentelle und pharmakokinetische Untersuchungen mit Gentamycin-PMMA-Kugeln.

Gentamicin PMMA beads (PMMA = polymethylmethacrylate) represent a new form of local antibiotic therapy for treating chronic bone and soft tissue infections. Gentamicin is released in high concentrations from PMMA. The therapeutic efficacy of the beads was demonstrated in a model of bone infection in dogs. Sufficiently high tissue concentrations of gentamicin were measurable for a period of 4 months. A very good tolerance of the beads was demonstrated in dogs as well as in cell cultures. High gentamicin concentrations exceeding the MBC values of relevant pathogens were measurable in patients at the site of infection. Serum and urine concentrations were low and therefore toxic side effects are excluded.

MIC determination, disc sensitivity testing, and analysis of regression in cefazedone and cefazolin.

Minimum inhibitory concentrations (MIC) of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl-a1-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen)), a new semisynthetic cephalosporin derivative were determined by a broth dilution technique. In comparison with cefazolin 130 gram-positive and gram-negative bacteria, recent clinical isolates, were tested. In parallel, inhibition zones for the same organisms were determined by a standardized disc technique using 30-micrograms discs. According to the calculated regression lines a good correlation was found for cefazedone and cefazolin between the MIC values and the diameters of the inhibition zones (correlation coefficients r = --0.90 and --0.92, respectively). Taking into account the dosages recommended for cefazedone and the mean serum concentrations to which they give rise, appropriate categories of sensitivity (break points) for susceptibility testing are recommended.

Blood levels and tissue concentrations of cefazedone in animals.

In mice, dogs, and rabbits blood and serum levels were evaluated after parenteral application of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen), cephalothin and cefazolin. In all three animal species cefazedone produced higher and more prolonged serum levels than did cefazolin. Evaluation of serum protein binding in mouse, dog and rabbit serum revealed marked differences between the species. Cefazedone and cefazolin tissue concentrations were evaluated in rabbits. Both antibiotics did not penetrate the CSF or brain tissue. In all other tissues examined (except bone marrow) higher and more prolonged tissue levels were attained with cefazedone than with cefazolin.

Comparison of cefazedone with cefazolin and cephalothin in treatment of experimental infections in mice.

The chemotherapeutic efficacy of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen) was assayed in comparison to cefazolin and cephalothin in experimental bacterial murine infections with 6 gram-positive and 8 gram-negative strains of the genera Staphylococcus, Streptococcus, Pneumococcus, Escherichia, Klebsiella, Proteus, Pasteurella and Salmonella. In 5 out of 14 strains (Staphylococci, Streptococci, E. coli, Klebsiella) cefazedone was markedly superior to cefazolin, whereas both compounds were of similar activity against the remaining 9 isolates. As compared to cephalothin, cefazedone exhibited highly superior effectiveness in all organisms tested.

The release of gentamicin from polymethylmethacrylate beads. An experimental and pharmacokinetic study.

Gentamicin incorporated in beads of polymethylmethacrylate has been shown capable of being released over a period of several months in concentrations sufficiently high to control most pathogens. The therapeutic efficacy of such beads has been demonstrated in a model of osteomyelitis of the femur in the dog. Good tolerance has been shown, both in the animal model and in tissue cultures. In forty-one patients with infection of either bone or soft tissue, mainly of the lower limb, the findings were similar. The concentrations in serum and urine were low, which excludes side-effects. The insertion of gentamicin-PMMA beads may prove to be a valuable new form of local antibiotic therapy.