Jim R. van Horn

Infection of orthopedic implants and the use of antibiotic-loaded bone cements - A review

Infections by bacteria are a serious complication following orthopedic implant surgery, that can usually only be cured by removing the implant, since the biofilm mode of growth of infecting bacteria on an implant surface protects the organisms from the host immune system and antibiotic therapy. Over the past few decades, attempts have been made to prevent and cure orthopedic implant infections by incorporating antibiotics in polymethylmethacrylate bone cements, in primary and revision surgery. However, the clinical efficacy of antibiotic-releasing bone cements is not accepted by all and the long-term exposure to low doses from antibiotic-releasing bone cements in patients is strongly related to the emerging threat of antibiotic resistance in medicine today. In this article, we start by reviewing the mechanisms governing the formation of an infectious biofilm on orthopedic implant materials, the release mechanisms and properties of clinically-used, antibiotic-loaded bone cements. The clinical efficacy of antibiotic-loaded bone cements is evaluated analyzing separatedly the prophylactic and therapeutic uses of these products.

Residual gentamicin-release from antibiotic-loaded polymethylmethacrylate beads after 5 years of implantation

In infected joint arthroplasty, high local levels of antibiotics are achieved through temporary implantation of non-biodegradable gentamicin-loaded polymethylmethacrylate beads. Despite their antibiotic release, these beads act as a biomaterial surface to which bacteria preferentially adhere, grow and potentially develop antibiotic resistance. In routine clinical practice, these beads are removed after 14 days, but for a variety of reasons, we were confronted with a patient in which these beads were left in situ for 5 years. Retrieval of gentamicin-loaded beads from this patient constituted an exceptional case to study the effects of long-term implantation on potentially colonizing microflora and gentamicin release. Gentamicin-release test revealed residual antibiotic release after being 5 years in situ and extensive microbiological sampling resulted in recovery of a gentamicin-resistant staphylococcal strain from the bead surface. This case emphasizes the importance of developing biodegradable antibiotic-loaded beads as an antibiotic delivery system.

Function and complications after ablative and limb-salvage therapy in lower extremity sarcoma of bone.

The functional results and the complications after several limb‐saving and ablative treatments because of lower extremity bone sarcoma were evaluated.

Gentamicin release from polymethylmethacrylate bone cements and Staphylococcus aureus biofilm formation

We measured the formation of a Staphylococcus aureus biofilm in vitro on unloaded and gentamicin-loaded bone cements (CMW3 and Palacos R) and related the formation to antibiotic release rates. All experiments were done in triplicate. Microbial growth on gentamicin-loaded cements occurred despite the release of antibiotic. Biofilm formation on gentamicin loaded CMW3 bone cement was one fourth to one fifth less than on the unloaded bone cement, while biofilm formation on Palacos R bone cement was not significantly affected by antibiotic loading. More gentamicin was released from CMW3 (79 mg) than from Palacos R (70 mg), but the percentage gentamicin released after one week relative to the total amount incorporated was significantly lower for CMW3 (4.7%) than for Palacos R (8.4%). After one day, subinhibitory concentrations of antibiotics were eluted from the cements. We concluded that antibiotic-loaded bone cement does not necessarily inhibit the formation of an infectious biofilm in vitro.

Comparison of analog and digital preoperative planning in total hip and knee arthroplasties. A prospective study of 173 hips and 65 total knees.

Introduction Digital correction of the magnification factor is expected to yield more accurate and reliable preoperative plans. We hypothesized that digital templating would be more accurate than manual templating for total hip and knee arthroplasties. Patients and methods Firstly, we established the interobserver and intraobserver reliability of the templating procedure. The accuracy and reliability of digital and analog plans were measured in a series of 238 interventions, which were all planned using both techniques. Results Interobserver reliability was good for the planning of knee arthroplasties (κ-values 0.63–0.75), but not more than moderate for the planning of hip arthroplasties (κ-values 0.22–0.54). Analog plans of knee arthroplasties systematically underestimated the component sizes (1.1 size on average), while the digital procedure proved to be accurate (0.1–0.4 size too small on average). The following figures show percentage of cases receiving a correct implant, allowing an error of one size. Digital templating of the hip arthroplasty was less frequently correct (cemented cup and stem: 72% and 79%; uncemented cup and stem: 52% and 66%) than analog planning (cemented cup and stem: 73% and 89%; uncemented cup and stem: 64% and 52%). Interpretation Planning of component sizes for total knee arthroplasties is an accurate procedure when performed digitally. Our digital preoperative plans which were performed by someone other than the surgeon were less accurate than the analog plans prepared by the surgeon.

The effect of mixing on gentamicin release from polymethylmethacrylate bone cements.

We compared the release of gentamicin from 6 different commercially available, antibiotic-loaded PMMA bone cements used for vacuum- and hand-mixed cement using a Cemvac vacuum mixing system. We also measured the release of gentamicin after manual addition of the antibiotic to different commercial, unloaded bone cements after hand-mixing. The porosity of cements was reduced in all vacuum-mixed cements, as compared with hand-mixed cements, concurrent with a statistically significant reduction (3 of 6) or increase (1 of 6) in the total amounts of gentamicin released. The total gentamicin release was studied in 3 of the brands after manual addition and mixing of the antibiotics. We found that the release of antibiotics was lower than in samples made from industrial mixing. In conclusion, the manual addition and mixing of gentamicin in PMMA bone cements leads to a lower release of antibiotics than that in corresponding commercially available antibiotic-loaded cements, while vacuum-mixing only leads to a minor reduction in antibiotic release, as compared to hand-mixing.

Pseudomonas aeruginosa biofilm formation and slime excretion on antibiotic-loaded bone cement

Background Infection is an infrequent but serious complication of prosthetic joint surgery. These infections will usually not clear until the implant is removed and re-implantation has a high failure rate, especially when Pseudomonas aeruginosa is involved. Material and methods We examined Pseudomonas aeruginosa biofilm formation on plain and gentami-cin-loaded bone cement with confocal scanning laser microscopy (CSLM). Two different stains were applied in order to visualize and quantify the distribution of bacterial cells and extracellular polymeric substances (slime) from the bone cement surface to the top of the biofilm. Staining with LIVE/DEAD viability stain differentiated between live and dead bacteria within the biofilm, and slime production was evaluated after staining with Calcofluor white. Results CSLM showed that the biofilm was a nonuniform structure of variable thickness, with differences in local bacterial cell and slime densities. Incorporation of gentamicin in bone cement resulted in a 44% reduction in bacterial viability, while the slime density increased significantly. In addition, conventional plate counting showed the development of small-colony variants on gentamicin-loaded bone cement with a decreased sensitivity for gentamicin (MIC: 8 mg/L), as compared with normal-sized colonies taken from plain and gentamicin-loaded bone cement (MIC: 3 mg/L). The enhanced slime production on antibiotic-loaded bone cement, together with the formation of small-colony variants, resulted in decreased susceptibility to antibiotics—probably concomitant with the onset of persistent and relapsing infections. Interpretation In the clinical situation, our findings help to explain the frequent re-implantation failure of joint replacements infected with P. aeruginosa when the procedure has been performed using antibiotic-loaded bone cement.

External and internal hemipelvectomy for sarcomas of the pelvic girdle: consequences of limb-salvage treatment

The outcome of different limb-saving treatment modalities for pelvic girdle sarcoma is controversial. The oncological and functional results after 11 external and 10 internal hemipelvectomies and the consequences of limb-salvage treatment were studied in 21 consecutive patients with primary bone (19 patients) or soft tissue sarcoma (two patients) of the pelvic girdle. Following external hemipelvectomy, 10 patients (91%) died after a median follow-up of 1.6 years (range: 0.3-7.1). Isolated local recurrences occurred in three patients (27%), with concomitant distant failure in one (9%), while isolated distant failure occurred in six patients (55%). The rate of flap necrosis and wound infection following external hemipelvectomy were both 25%. Following internal hemipelvectomy, nine patients (90%) were alive without evidence of disease after a median follow-up of 6.6 years (range: 2.3-16.0). Concomitant local and distant failures were found in one patient (10%). Reconstruction-related complications necessitated revisional procedures in five of seven patients (72%), leading to external hemipelvectomy in one. Patients with a locally advanced pelvic girdle sarcoma who are unable to undergo an internal hemipelvectomy have a worse prognosis than patients who undergo an internal hemipelvectomy. An internal hemipelvectomy is not attended by an increased risk of local failure, but is by long-term local complications, requiring extensive surgical procedures.

Scoliosis correction with shape-memory metal: results of an experimental study

Abstract. The biocompatibility and functionality of a new scoliosis correction device, based on the properties of the shape-memory metal nickel-titanium alloy, were studied. With this device, the shape recovery forces of a shape-memory metal rod are used to achieve a gradual three-dimensional scoliosis correction. In the experimental study the action of the new device was inverted: the device was used to induce a scoliotic curve instead of correcting one. Surgical procedures were performed in six pigs. An originally curved squared rod, in the cold condition, was straightened and fixed to the spine with pedicle screws. Peroperatively, the memory effect of the rod was activated by heating the rod to 50°C by a low-voltage, high-frequency current. After 3 and after 6 months the animals were sacrificed. The first radiographs, obtained immediately after surgery, showed in all animals an induced curve of about 40° Cobb angle – the original curve of the rod. This curve remained constant during the follow-up. The postoperative serum nickel measurements were around the detection limit, and were not significantly higher compared to the preoperative nickel concentration. Macroscopic inspection after 3 and 6 months showed that the device was almost overgrown with newly formed bone. Corrosion and fretting processes were not observed. Histologic examination of the sections of the surrounding tissues and sections of the lung, liver, spleen and kidney showed no evidence of a foreign body response. In view of the initiation of the scoliotic deformation, it is expected that the shape-memory metal based scoliosis correction device also has the capacity to correct a scoliotic curve. Moreover, it is expected that the new device will show good biocompatibility in clinical application. Extensive fatigue testing of the whole system should be performed before clinical trials are initiated.

Concepts for increasing gentamicin release from handmade bone cement beads

Background and purpose Commercial gentamicin-loaded bone cement beads (Septopal) constitute an effective delivery system for local antibiotic therapy. These beads are not available in all parts of the world, and are too expensive for frequent use in others. Thus, orthopedic surgeons worldwide make antibiotic-loaded beads themselves. However, these beads are usually not as effective as the commercial beads because of inadequate release kinetics. Our purpose was to develop a simple, cheap, and effective formulation to prepare gentamicin-loaded beads with release properties and antibacterial efficacy similar to the commercially ones. Methods Acrylic beads were prepared with variable monomer content: 100% (500 µL/g polymer), 75%, and 50% to increase gentamicin release through creation of a less dense polymer matrix. Using the optimal monomer content, different gel-forming polymeric fillers were added to enhance the permeation of fluids into the beads. Polyvinylpyrrolidone (PVP) 17 was selected as a suitable filler; its concentration was varied and the antibiotic release and antibacterial efficacy of these beads were compared with the corresponding properties of the commercial ones. Results Gentamicin release rate and the extent of release from beads prepared with 50% monomer increased when the PVP17 content was increased. Beads with 15 w/w% PVP17 released 87% of their antibiotic content. This is substantially more than the gentamicin release from Septopal beads (59%). Acrylic beads with 15 w/w% PVP17 reduced bacterial growth by up to 93%, which is similar to the antibacterial properties of the commercial ones. Interpretation A simple, cheap, and effective formulation and preparation process has been described for hand-made gentamicin-releasing acrylic beads, with better release kinetics and with antibacterial efficacy similar to that of the commercial ones.