Antibiotic elution from acrylic bone cement loaded with high doses of tobramycin and vancomycin

Two‐stage revision treatment of prosthetic joint infection (PJI) frequently employs the use of a temporary bone cement spacer loaded with multiple antibiotic types. Tobramycin and vancomycin are commonly used antibiotics in cement spacers, however, there is no consensus on the relative concentrations and combinations that should be used. Therefore, the purpose of this study was to investigate the influence of dual antibiotic loading on the total antibiotic elution and compressive mechanical properties of acrylic bone cement. Varying concentrations of tobramycin (0–3 g) and vancomycin (0–3 g) were added either alone or in combination to acrylic cement (Palacos R), resulting in 12 experimental groups. Samples were submerged in 37°C saline for 28 d and sampled at specific time points. The collected eluent was analyzed to determine the cumulative antibiotic release. In addition, the cement's compressive mechanical properties and porosity were characterized. Interestingly, the cement with the highest concentration of antibiotics did not possess the best elution properties. Cement samples containing both 3 g of tobramycin and 2 g vancomycin demonstrated the highest cumulative antibiotic release after 28 d, which was coupled with a significant decrease in the mechanical properties and an increased porosity. The collected data also suggests that tobramycin elutes more effectively than vancomycin from cement. In conclusion, this study demonstrates that high antibiotic loading in cement does not necessarily lead to enhanced antibiotic elution. Clinically this information may be used to optimize cement spacer antibiotic loading so that both duration and amount of antibiotics eluted are optimized. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1078–1085, 2018.

     

Prechilling and vacuum mixing not suitable for all bone cements: Handling characteristics and exotherms of bone cements

Nine bone cements were tested for handling characteristics, intrusion, doughing time, setting time, and exothermic temperature. Comparative studies were made of manual mixing and vacuum mixing of cement components stored at room temperature or chilled to 5 degrees C. Vacuum mixing of cement packages stored at room temperature was inapplicable except for the low-viscosity brands, as the cements became too viscous to mold test specimens. Prechilling and vacuum mixing prolonged the setting time and preserved a lower viscosity during the handling period. Palacos R and Palacos G were most suitable for this method, whereas a considerable increase in exothermic temperature was experienced with the other brands. The method might, however, be considered for Zimmer and Cerafix also, as the exotherm was of the same magnitude as for Palacos brands.     

Antibiotic-free antimicrobial poly (methyl methacrylate) bone cements: A state-of-the-art review

Prosthetic joint infection (PJI) is the most serious complication following total joint arthroplasty, this being because it is associated with, among other things, high morbidity and low quality of life, is difficult to prevent, and is very challenging to treat/manage. The many shortcomings of antibiotic-loaded poly (methyl methacrylate) (PMMA) bone cement (ALBC) as an agent for preventing and treating/ managing PJI are well-known. One is that microorganisms responsible for most PJI cases, such as methicillin-resistant S. aureus, have developed or are developing resistance to gentamicin sulfate, which is the antibiotic in the vast majority of approved ALBC brands. This has led to many research efforts to develop cements that do not contain gentamicin (or, for that matter, any antibiotic) but demonstrate excellent antimicrobial efficacy. There is a sizeable body of literature on these so-called “antibiotic-free antimicrobial” PMMA bone cements (AFAMBCs). The present work is a comprehensive and critical review of this body. In addition to summaries of key trends in results of characterization studies of AFAMBCs, the attractive features and shortcomings of the literature are highlighted. Shortcomings provide motivation for future work, with some ideas being formulation of a new generation of AFAMBCs by, example, adding a nanostructured material and/or an extract from a natural product to the powder and/or liquid of the basis cement, respectively.     

抗生素骨水泥和连续灌注治疗关节置换后感染

目的　为人工关节置换术后感染探索新的治疗方法。方法　回顾 68例人工关节置换手术 ,发生术后感染 10例 ,其中全膝关节置换术后感染 4例 ,全髋关节置换术后感染 6例 ,全部采用抗生素骨水泥同时采用抗生素连续灌注。结果　病程在 2周内的 4例用此方法全部保留假体成功 ,其余 6例病程都在 4周以上 ,保留假体失败。结论　关节置换术后感染是严重并发症 ,本方法是一种保留假体的补救措施。     

An articulated antibiotic spacer used for infected total knee arthroplasty: a comparative in vitro elution study of Simplex and Palacos bone cements.

For the staged management of infected total knee arthroplasty (TKA), antibiotic laden polymethylmethacrylate (PMMA) spacers have been recommended. Antibiotic-impregnated PMMA spacers target drug delivery, achieving high local levels while limiting the potential for host toxicity associated with parenteral antimicrobial therapy. This study examined the elution characteristics of an articulating PMMA TKA spacer that has been useful clinically. Tobramycin and vancomycin are both active against many organisms leading to joint infections. We used various combined antibiotic concentrations (maintaining a relative ratio of 55% tobramycin to 45% vancomycin w/w), and then assayed the elution profile of the TKA spacer in vitro. Additionally, the elution qualities of two brands of bone cement, Simplex and Palacos, were compared. Briefly, three groups of PMMA spacers, impregnated with different antibiotic loads, were fashioned from a mold replicating a femoral TKA component. The entire spacer surface area was immersed in sterile phosphate buffered saline (PBS) in a 1:6 ratio of grams of cement to milliliters of PBS and incubated at 37 degrees C for 24 h. After 24 h, aliquot eluates were taken, the PBS discarded, and replaced with fresh, sterile PBS. PBS was changed daily and an aliquot was taken at least weekly for nine weeks. Eluate samples were stored at -70 degrees C until assayed. Each spacer eluate sample's antibiotic concentration was determined by disc diffusion bioassay against Bacillus subtilis. Mean zone inhibition diameters were extrapolated from the standard curve to yield micrograms per milliliter of antibiotic in PBS. In all groups the Palacos spacers demonstrated higher elution levels, above the MIC for the organism used, for a longer period of time than those made with Simplex. Based on the observed elution profiles, antibiotic-impregnated Palacos bone cement may offer a more effective vehicle for local drug delivery during staged treatment of infected TKA.     

Elution and mechanical properties of antifungal bone cement

The effect of the incorporation of amphotericin B into bone cement was examined; as literature suggests, this may be a feasible method for the treatment of periprosthetic fungal infections. Addition of antifungal increased the compressive strength of the bone cement--a statistically significant amount from 107 +/- 2.3 to 121 +/- 1.5 MPa. Elution of tobramycin and amphotericin B was quantified using ultraviolet-visible spectroscopy. Spectroscopy showed that 18% of the antibiotic was released during the first week, with most released in the first 24 hours. The elution of antifungal, however, was unable to be detected after 1 week, with less than 0.03% released. Amphotericin B does not weaken bone cement. Its inability to be delivered at a clinically significant dose gives no clear indication for its incorporation into cement.     

Successful Treatment of Candida Albicans–Infected Total Hip Prosthesis With Staged Procedure Using an Antifungal-Loaded Cement Spacer

We present a rare case of an immunocompetent host who developed a Candida albicans–infected total hip prosthesis. The infection could not be eradicated with debridement and extensive antifungal therapy. Our patient first underwent a resection of the proximal femur and local treatment with gentamicin-loaded cement beads. In a second procedure, a handmade cement spacer impregnated with voriconazole, amphotericin B, and vancomycin was placed. After 3 months of additional systemic antibiotic therapy, the patient remained afebrile, and a tumor prosthesis was placed. Six years postoperatively, she is doing well, walking with a small limp and no signs of recurrent infection. This is the first report on elution of voriconazole and amphotericin B from bone cement delivered at clinically significant concentrations for at least 72 hours.     

A modified cement spacer technique for infected total hip arthroplasties with significant bone loss

Complications related to femoral spacers are common during addressing infected total hip arthroplasties by 2-stage revision. We evaluated 11 patients who had 2-stage revisions with massive bone loss after removal of the infected components by a trochanteric osteotomy. All femoral cement spacers were assembled on intramedullary nails. Femurs were protected by a plate, whereas acetabuli were augmented by a cage or roof ring depending on the remaining bone stock. This additional hardware was covered with antibiotic-impregnated cement. Infection was eradicated in 10 (90.9%) of 11 patients within 3.5 months in average. None of the patients had spacer fracture, periprosthetic fracture, or dislocation. Augmentation by hardware covered with antibiotic-impregnated cement is effective and may reduce complications until definitive treatment is performed.     

髋关节抗生素骨水泥占位器的研究进展

感染可能是外科植入体如人工假体、髓内针、钢板的严重并发症。尽管围手术期给予适当的抗生素,但仍有相当数量患者术后发生假体周围感染(PJI)。感染的结果导致过度使用抗生素、假体移除、再手术和可能的截肢。当前,PJI通常很难预测、诊断和治疗,二期翻修术是治疗PJI的合理选择。本文仅对髋关节临时占位器(spacer)的有关研究进展作一综述。     

Microencapsulation of rifampicin: A technique to preserve the mechanical properties of bone cement

Two‐stage exchange with antibiotic‐loaded bone cement spacers remains the gold standard for chronic periprosthetic joint infection (PJI). Rifampicin is highly efficient on stationary‐phase staphylococci in biofilm; however, its addition to PMMA to manufacture spacers prevents polymerization and reduces mechanical properties. Isolation of rifampicin during polymerization by microencapsulation could allow manufacturing rifampicin‐loaded bone cement maintaining elution and mechanical properties. Microcapsules of rifampicin with alginate, polyhydroxybutyratehydroxyvalerate (PHBV), ethylcellulose and stearic acid (SA) were synthesized. Alginate and PHBV microcapsules were added to bone cement and elution, compression, bending, hardness, setting time and microbiological tests were performed. Repeated measures ANOVA and Bonferroni post‐hoc test were performed, considering a p < 0.05 as statistical significance. Bone cement specimens containing alginate microcapsules eluted more rifampicin than PHBV microcapsules or non‐encapsulated rifampicin over time (p < 0.012). Microencapsulation of rifampicin allowed PMMA to preserve mechanical properties in compression and bending tests. Cement with alginate microcapsules showed similar behavior in hardness tests to control cement over the study period (73 ± 1.68H_D). PMMA with alginate microcapsules exhibited the largest zones of inhibition in microbiological tests. Statistically significant differences in mean diameters of zones of inhibition between PMMA loaded with alginate‐rifampicin (p = 0.0001) and alginate‐PHBV microcapsules (p = 0.0001) were detected. Rifampicin microencapsulation with alginate is the best choice to introduce rifampicin in PMMA preserving mechanical properties, setting time, elution, and antimicrobial properties. The main applicability of this study is the opportunity for obtaining rifampicin‐loaded PMMA by microencapsulation of rifampicin in alginate microparticles, achieving high doses of rifampicin in infected tissues, increasing the successful of PJI treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:459–466, 2018.

     

Experimental study of apatite cement containing antibiotics

Long-term systemic administration of high concentrations of antibiotics may have adverse effects on local osmolality and on various organs; the potential for such effects provides a rationale for the direct administration of such drugs to local sites. The ideal material for this purpose should contain adequate amounts of antibiotics and be biocompatible, and be capable of filling bone defects. We used an implant material called apatite cement. Compounded with gentamyicin (GM) and poly-l-lactic acid (PLA), this material has excellent biocompatibility. In vitro and in vivo studies of this new compound (52 Japanese white house rabbits) showed that the release of antibiotic was gradual and that an effective drug concentration was maintained for 2 months. Histologic findings revealed new bone formation from 2 weeks after implantation. Thereafter, new bone formation sequentially increased in volume. Within 24 weeks, new bone was identified even inside cracked implants. The implant we developed was composed of bioactive material and delivered antibiotic at a level that exceeded the minimal inhibitory concentration ofStaphylococcus aureus. Our implant appears to stimulate satisfactory bone formation. An abstract of this paper was presented at the 9th International Symposium on Ceramics in Medicine and the 9th Basic Research Session of the Japanese Society of Orthopedic Surgery     

Comprehensive meta-analysis of antibiotic-impregnated bone cement versus plain bone cement in primary total knee arthroplasty for preventing periprosthetic joint infection

PurposeAntibiotic-loaded bone cement (ALBC) was usually used to prevent periprosthetic joint infection (PJI) in primary total knee arthroplasty (PTKA), but whether to use ALBC or plain bone cement in PTKA remains unclear. We aimed to compare the occurrence rate of PJI using two different cements, and to investigate the efficacy of different antibiotic types and doses administered in preventing surgical site infection (SSI) with ALBC.MethodsThe availability of ALBC for preventing PJI was evaluated by using a systematic review and meta-analysis referring to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Existing articles until December 2021 involving PTKA patients with both ALBC and plain bone cement cohorts were scanned by searching “total knee arthroplasty”, “antibiotic-loaded cement”, “antibiotic prophylaxis”, “antibiotic-impregnated cement” and “antibiotic-laden cement” in the database of PubMed/MEDLINE, Embase, Web of Science and the Cochrane Library. Subgroup analysis included the effectiveness of different antibiotic types and doses in preventing SSI with ALBC. The modified Jadad scale was employed to score the qualities of included articles.ResultsEleven quantitative studies were enrolled, including 34,159 knees undergoing PTKA. The meta-analysis results demonstrated that the use of prophylactic ALBC could significantly reduce the prevalence of deep incisional SSI after PTKA, whereas there was no significant reduction in the rate of superficial incisional SSI. Moreover, gentamicin-loaded cement was effective in preventing deep incisional SSI, and the use of high-dose ALBC significantly reduced the rate of deep incisional SSI after PTKA. Besides, no significant adverse reactions and complications were stated during the use of ALBC in PTKA.ConclusionThe preventive application of ALBC during PTKA could reduce the rates of deep PJI. Furthermore, bone cement containing gentamicin and high-dose ALBC could even better prevent deep infection after PTKA. However, the existing related articles are mostly single-center and retrospective studies, and further high-quality ones are needed for confirmation.     

When and How Should I Use Antibiotic Cement in Primary and Revision Joint Arthroplasty?

Periprosthetic joint infections (PJIs) remain one of the most challenging and devastating complications associated with total joint arthroplasty. Therefore, prevention and the ability to effectively treat PJIs are critical. One such tool for both the prevention and treatment of PJIs is the use of antibiotic-loaded bone cement (ALBC). ALBC provides an effective local delivery method of antibiotics. Low dose (<2 g per 40-g batch) is commonly used for prophylaxis, while high dose (>3.6 g per 40-g batch) is used for the treatment of PJIs. This review focuses on the efficacy, safety, and cost-effectiveness of ALBC for both the prevention as well as the treatment of PJIs.     

Repeat 2-Stage Revision for Recurrent Infection of Total Hip Arthroplasty

Eleven patients who developed reinfection after 2-stage revision for infected total hip arthroplasty (THA) were treated with a repeat 2-stage rerevision. Of the 11 rerevisions, 4 were successful, with no recurrent infection at mean follow-up of 44 months. Reinfection occurred in 7 patients of whom 6 involved either a significantly compromised host or poor local wound status. Clinical symptoms of infection were controlled in 4 of the 7 reinfected cases with antibiotic therapy in 2, irrigation and debridement in 1, and a third 2-stage revision THA in 1. Repeat 2-stage treatment of infected THA is associated with a high failure rate. However, successful results can be achieved particularly if the host is not immunocompromised and healthy soft tissue coverage is present.     

In vitro release of antibiotics from commercial PMMA beads and articulating hip spacers

The efficacy and benefits of high-dose antibiotic cement spacers compared with beads in the treatment of an infected prosthesis have been shown. However, in clinical practice, commercial, low-dose antibiotic bone cement is often used. This study investigated the in vitro antibiotic release of hip spacers made from Refobacin-Palacos-R or Antibiotic-Simplex-P cement compared with Septopal beads. Antibiotic concentrations were measured during 6 weeks. All carriers showed a burst release, but spacers showed little additional release after the first week. Cumulative release was 27.5 +/- 2.3 mg for Palacos, 23.8 +/- 0.2 mg for Simplex, and 188.3 +/- 9.3 mg for Septopal (P < .001). Despite the efficacy of high-dose antibiotic bone cement spacers, we believe one should be cautious toward using low-dose antibiotic bone cement for spacers because this could result in an unsuccessful eradication of infection.     

The Hidden Cost of Commercial Antibiotic-Loaded Bone Cement: A Systematic Review of Clinical Results and Cost Implications Following Total Knee Arthroplasty

Background

The purpose of this systematic review is to compare deep prosthetic joint infections (PJIs) between total knee arthroplasty (TKA) patients treated with either antibiotic-loaded bone cement (ALBC) or plain bone cement, and to explore the potential cost implications of commonly used bone cement regimens. We hypothesized that ALBC would not substantially reduce PJIs and would thereby present an unnecessary cost to the healthcare system.

多孔载因子CPC促进骨缺损愈合的实验研究

[目的]探讨磷酸钙骨水泥复合rhBMP-2/明胶微球复合材料在治疗骨缺损时的降解、成骨性能。[方法]制备携载rhBMP-2的明胶微球(GMs),与磷酸钙骨水泥(CPC)复合,制备出rhBMP-2/GMs/CPC复合人工骨。取30只新西兰大白兔,在前臂桡骨中段制造人工骨缺损,随机分成3组,分别植入rhBMP-2/GMs/CPC/复合物(A组)、GMs/CPC(B组)、rhBMP-2/CPC(C组),术后6、12周分别进行X线检测、骨密度测定,术后12周处死动物,分别行生物力学测定,脱钙切片、HE染色,不脱钙切片进行荧光显微镜下观察双标间距,计算平均矿化率。[结果]与GMs/CPC、rhBMP-2/CPC组比较,复合材料植入后不同时间点的材料降解及成骨均高于对照组。12周A组标本生物力学实验测定结果表明指标接近正常,与B、C组比较有统计学差异。骨密度12周、新骨矿化率提示有统计学差异。[结论]rhBMP-2/GMs/CPC微球系统复合材料在体内易降解,具有良好成骨活性,是良好的骨修复材料。     

Sustained pressurization of polymethylmethacrylate: a comparison of low- and moderate-viscosity bone cements

There is at present great uncertainty relating to the fixation of joint implants. The deficiencies of acrylic bone cement are well documented, but the limitations of cementless fixation are as yet imcompletely identified. The purpose of this study was to investigate the potential of sustained external pressurization to improve the mechanical characteristics of conventional acrylic bone cement. The effect of serially increasing sustained pressurization of two commerically available acrylic bone cements (Simplex-P and LVC) was evaluated in human cadaver femora. A new method for determination of the shear strength of the bone-cement interface in place of the traditional pushout tests was used. In this model, there was a significant increase in the bone-cement interfacial shear strength with increasing pressure, but no difference in the shear strength was found between the two cements. At all pressure levels, the shear strength of the cement was greater than that previously reported. Increased cement penetration into the cortical bone was demonstrated with increasing pressure and low-viscosity cement, but the extent of cement penetration did not correlate with the shear strength of the bone-cement interface.     

Antibiotic-loaded cement articulating spacer for 2-stage reimplantation in infected total knee arthroplasty: a simple and economic method

We presented a simple and economic method of preparing articulating antibiotic-loaded cement spacers for treatment of infection after total knee arthroplasty. From 1996 to 2004, 28 infected total knee arthroplasties were treated with 2-stage reimplantation. Static spacers were used in 7 knees, and articulating spacers were used in 21 knees. A minimum of 2 years' follow-up after final treatment was evaluated. In the static group, 1 (14%) knee had recurrence of infection. In the articulating group, 2 (9%) knees had recurrence of infection with the original organism. Patients receiving articulating spacer had better range of motion, better knee score, and less bone loss than patients with static spacer.     

Initial results of managing severe bone loss in infected total joint arthroplasty using customized articulating spacers

Twenty-three cases of infected total joint arthroplasty with substantial bone loss were treated with a cement spacer, which was customized intraoperatively to achieve joint stability and to allow motion. All but one of the patients were ambulatory with the spacer in place. Spacer dislocation occurred in 1 hip patient (9%) and in none of the knee patients. Articulating antibiotic-impregnated spacers with intraoperative customization is our preferred treatment of cases of infected total joint arthroplasty even in the presence of bone loss.