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Effect of Trabecular Metal on the Elution of Gentamicin from Palacos Cement
Abstract
Periprosthetic joint infections continues to be a common complication in total joint arthroplasty, resulting in significant morbidity, mortality and additional costs. Antibiotic loaded bone cement has profoundly reduced the incidence of infection and revision. Trabecular metal implants with an internal cemented interface may be customizable drug delivery devices with an ingrowth interface. Thirty‐six acetabular implants were assembled in vitro, half with a trabecular metal shell and half without. The antibiotic loaded bone cement was prepared via three different mixing techniques and at two mixing times. Mixing time had a significant effect on the total amount of gentamicin eluted. The long mix protocol eluted up to 126% (p = 0.001) more gentamicin than the short mix at four hours and 192% (p < 0.001) more at seven days. The use of a trabecular metal shell had no significant effect at four hours (p > 0.05) but significantly reduced total elution under certain mixing protocols at seven days. Mixing technique had no significant effect on elution at four hours. At seven days, the mechanical mixing system under vacuum eluted over 50% (p = 0.031) more antibiotic than without a vacuum and nearly 60% (p = 0.040) more antibiotic than hand mixing. The use of trabecular metal implants does not significantly inhibit the initial bulk elution of gentamicin. A possible optimization strategy to improve elution kinetics would be to use a long mixing time with a mechanical mixing system under vacuum. This article is protected by copyright. All rights reserved
... A long mixing time (mixing 90 s, doughing 30 s) significantly enhanced drug elution compared with a short mixing time (mixing 30 s, doughing 90 s) in gentamycin-loaded ALBC, and an obvious increase in total drug elution of 7 days was detected in the vacuum mixing group. [31] (4) Environment temperature: Lower temperature extends the polymerization reaction, causing an increase of air pore collected in cement matrix. So, it will be easier for antibiotic particles to penetrate the cement. ...
Bone cement, consisting of polymethyl methacrylate, is a bioinert material used for prothesis fixation in joint arthroplasty. To treat orthopedic infections, such as periprosthetic joint infection, antibiotic-loaded bone cement (ALBC) was introduced into clinical practice. Recent studies have revealed the limitations of the antibacterial effect of ALBC. Moreover, with the increase in high infection risk patients and highly resistant microbes, more researches and modification of ALBC are required. This paper reviewed latest findings about ALBC for most popular and destructive pathogens, summarized the influence of antibiotic kind, drug dosage, application method, and environment towards characteristic of ALBC. Subsequently, new cement additives and clinical applications of ALBC in joint arthroplasty were also discussed.
Self-defensive biomaterial surfaces are being developed in order to mitigate infection associated with tissue-contacting biomedical devices. Such infection occurs when microbes colonize the surface of a device and proliferate into a recalcitrant biofilm. A key intervention point centers on preventing the initial colonization. Incorporating antimicrobials within a surface coating can be very effective, but the traditional means of antimicrobial delivery by continuous elution can often be counterproductive. If there is no infection, continuous elution creates conditions that promote the development of resistant microbes throughout the patient. In contrast, a self-defensive coating releases antimicrobial only when and only where there is a microbial challenge to the surface. Otherwise, the antimicrobial remains sequestered within the coating and does not contribute to the development of resistance. A self-defensive surface requires a local trigger that signals the microbial challenge. Three such triggers have been identified as: (1) local pH lowering; (2) local enzyme release; and (3) direct microbial-surface contact. This short review highlights the need for self-defensive surfaces in the general context of the device-infection problem and then reviews key biomaterials developments associated with each of these three triggering mechanisms.
Around about 1970, a gentamicin-loaded poly (methylmethacrylate) (PMMA) bone cement brand (Refobacin Palacos R) was introduced to control infection in joint arthroplasties. In 2005, this brand was replaced by two gentamicin-loaded follow-up brands, Refobacin Bone Cement R and Palacos R + G. In addition, another gentamicin-loaded cement brand, SmartSet GHV, was introduced in Europe in 2003. In the present study, we investigated differences in gentamicin release and the antibacterial efficacy of the eluent between these four cement brands.
200 μm-wide gaps were made in samples of each cement and filled with buffer in order to measure the gentamicin release. Release kinetics were related to bone cement powder particle characteristics and wettabilities of the cement surfaces. Gaps were also inoculated with bacteria isolated from infected prostheses for 24 h and their survival determined. Gentamicin release and bacterial survival were statistically analysed using the Student's t-test.
All three Palacos variants showed equal burst releases but each of the successor Palacos cements showed significantly higher sustained releases. SmartSet GHV showed a significantly higher burst release, while its sustained release was comparable with original Palacos. A gentamicin-sensitive bacterium did not survive in the high gentamicin concentrations in the interfacial gaps, while a gentamicin-resistant strain did, regardless of the type of cement used. Survival was independent of the level of burst release by the bone cement.
Although marketed as the original gentamicin-loaded Palacos cement, orthopaedic surgeons should be aware that the successor cements do not appear to have the same release characteristics as the original one. Overall, high gentamicin concentrations were reached inside our prosthesis-related interfacial gap model. These concentrations may be expected to effectively decontaminate the prosthesis-related interfacial gap directly after implantation, provided that these bacteria are sensitive for gentamicin.
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.
Contemporary mixing methods-centrifugation, vacuum mixing with or without precompression-were compared with manual mixing by testing strength characteristics in accordance with a proposed revision of the international standard for bone cements as applied to 10 cement brands.Simplex® brands and low-viscosity cements were the strongest, and were not improved by any of the vacuum-mixing procedures. Centrifuging was found unsuitable for low-viscosity cements.Without attaining the strength of the former, the cements best suited for auxiliary mixing methods were CMW-1 ® and Palacos ® brands, which improved 6-11 percent by either of the methods. The Sterivac® system was generally found unacceptable, because about 20 percent of a cement package was retained in the mixing gear, and the application of precompression had no additional effect on compressive and bending strengths.
Periprosthetic joint infection (PJI) represents substantial clinical and economic burdens. This study evaluated patient and procedure characteristics and resource utilization associated with revision arthroplasty for PJI. The Nationwide Inpatient Sample (Q4 2005-2010) was analyzed for 235,857 revision THA (RTHA) and 301,718 revision TKA (RTKA) procedures. PJI was the most common indication for RTKA, and the third most common reason for RTHA. PJI was most commonly associated with major severity of illness (SOI) in RTHA, and with moderate SOI in RTKA. RTHA and RTKA for PJI had the longest length of stay. Costs were higher for RTHA/RTKA for PJI than for any other diagnosis except periprosthetic fracture. Epidemiologic differences exist in the rank, severity and populations for RTHA and RTKA for PJI.
Copyright © 2015. Published by Elsevier Inc.
We evaluated the effects of the mixing speed of hand-mixed bone cement and the different phases of antibiotic mixing on the elution, mechanical properties, and porosity of antibiotic-loaded bone cement. Vancomycin-loaded Palacos LV bone cement was prepared at two hand-mixing speeds, normal and high-speed, and with antibiotic addition during three phases (directly mixing with the PMMA powder, in the liquid phase, and in the dough phase). The cumulative antibiotic elution over 15days in the high-speed group was increased by 24% compared with the normal-speed group (P<0.001). The delayed antibiotic addition produced higher vancomycin elution (P<0.05), but no difference was observed between the liquid and dough phases (P>0.05). Our study demonstrated that bone cement prepared with high-speed hand mixing and delayed antibiotic addition can exhibit increased vancomycin release.
Copyright © 2014. Published by Elsevier Inc.
Antibiotic-loaded acrylic bone cements (ALABC) spacers are routinely used in the treatment of prosthetic joint infections. The objectives of our study were to evaluate different ALABC for elution kinetics, thermal stability, and mechanical properties. A 10 or 20% mixture (w/w) beads of medium viscosity bone cement (DePuy, Inc) and vancomycin (VAN), gentamycin (GM), daptomycin (DAP), moxifloxacin (MOX), rifampicin (RIF), cefotaxime (CTX), cefepime (FEP), amoxicillin clavulanate (AmC), ampicillin (AMP), meropenem (MER), and ertapenem (ERT) were formed and placed into wells filled with phosphate-buffered saline. Antibiotic concentrations were determined using high-performance liquid chromatography. Antimicrobial activity was tested against Micrococcus luteus ATCC 9341 or Escherichia coli ATCC 25922. AmC, AMP, and FEP concentration rapidly decreased after day 2, being almost undetectable at day 4. Sustained and high elution rates were observed with VAN, GM, MOX, and RIF for the 30-day duration of the experiment. DAP, MER, ERT, and CTX elution rates constantly decreased from day 4. All antibiotics tested retained antimicrobial activity proving thermal stability. Mechanical properties of ALABC were maintained except when RIF was used.
Human use of antimicrobials in the clinic, community and agricultural systems has driven selection for resistance in bacteria. Resistance can be selected at antibiotic concentrations that are either lethal or non-lethal, and here we argue that selection and enrichment for antibiotic resistant bacteria is often a consequence of weak, non-lethal selective pressures - caused by low levels of antibiotics - that operates on small differences in relative bacterial fitness. Such conditions may occur during antibiotic therapy or in anthropogenically drug-polluted natural environments. Non-lethal selection increases rates of mutant appearance and promotes enrichment of highly fit mutants and stable mutators.
Evidence-based medicine indicates the use of antibiotic-impregnated polymethylmethacrylate bone cement during hip and knee replacement reduces the rate of prosthetic joint infection. In the United States, so-called off-label use of antibiotic-impregnated polymethylmethacrylate for primary joint replacement is increasing and multiple antibiotic-containing polymethylmethacrylate products are commercially available. However, there are sparse published data comparing the antibiotic elution characteristics of these bone cement products and the effect that vacuum-mixing has on antibiotic elution from these products. This study compares the antibiotic elution characteristics of six commercially available antibiotic polymethylmethacrylate formulations mixed under atmospheric pressure and vacuum conditions.
The antibiotic-impregnated polymethylmethacrylate products were mixed with use of a commonly employed intraoperative technique at atmospheric pressure and clinically relevant vacuum conditions. A standard Kirby-Bauer bioassay technique was subsequently used to quantify antibiotic elution from the products. An international infectious disease database was mined to determine antibiotic susceptibility of common bacteria causing prosthetic joint infection and to define the gentamicin concentration above which optimal antibiotic efficacy begins for these organisms. Statistical analyses incorporating the above susceptibility data were performed to compare antibiotic elution (1) among products mixed at atmospheric pressure, (2) among vacuum-mixed products, and (3) between atmospheric and vacuum-mixing for each individual product.
Comparisons of antibiotic-loaded polymethylmethacrylate products mixed at atmospheric pressure indicated that significant antibiotic elution differences exist among the products. Comparisons of vacuum-mixed antibiotic-loaded polymethylmethacrylate products indicated that significant antibiotic elution differences exist among the products. When mixing under atmospheric pressure was compared with vacuum-mixing for each individual antibiotic polymethylmethacrylate product, vacuum-mixing significantly increased the clinically relevant cumulative antibiotic elution from three products but significantly decreased antibiotic elution from three other products.
The method by which antibiotic-containing polymethylmethacrylate products are prepared significantly affects their antibiotic elution characteristics. The effect of vacuum-mixing on antibiotic elution is product-specific.
Contemporary mixing methods--centrifugation, vacuum mixing with or without precompression--were compared with manual mixing by testing strength characteristics in accordance with a proposed revision of the international standard for bone cements as applied to 10 cement brands. Simplex brands and low-viscosity cements were the strongest, and were not improved by any of the vacuum-mixing procedures. Centrifuging was found unsuitable for low-viscosity cements. Without attaining the strength of the former, the cements best suited for auxiliary mixing methods were CMW-1 and Palacos brands, which improved 6-11 percent by either of the methods. The Sterivac system was generally found unacceptable, because about 20 percent of a cement package was retained in the mixing gear, and the application of precompression had no additional effect on compressive and bending strengths.
Polymethylmethacrylate bone cement, containing either no added antibiotic, 0.5 g of Vancomycin, 1.0 g of Vancomycin, or 1.0 g of Tobramycin, was mixed either in air or a vacuum chamber. Following storage in a water bath at 37 degrees C for 48 h, the specimens were tested in four-point bending. The porosity of the specimens was assessed radiographically, and their antibacterial activity was monitored for 21 days. The bending strength of the vacuum mixed specimens containing no antibiotic was 40% greater than that of similar air-mixed specimens. However, there were no significant differences in the bending strength of either the air- or vacuum-mixed specimens when any of the antibiotic dosages were added. The bending modulus of the vacuum-mixed specimens, containing no antibiotic, was significantly greater than the moduli of all the other specimen groups which did not differ from each other. Vacuum mixing reduced the apparent porosity of the specimens fivefold, and while the addition of antibiotic did not effect porosity of the air-mixed specimens, that of the vacuum-mixed specimens was doubled. Although initial rapid decreases were seen, leaching of antibiotic from the cement and antibacterial activity continued through the 21-day monitoring period.
Conventional mixing of three different bone cements (CMW, Simplex P, and Zimmer LVC) was compared with a mechanical technique with respect to porosity and density. Density was increased in all the mechanically mixed cements, and the percentage porosity was diminished for CMW and Simplex P.
Polymethylmethacrylate loaded with antimicrobial agents (most commonly vancomycin and/or aminoglycosides) is used for treatment and prevention of orthopaedic infections. Emergence of organisms resistant to vancomycin or aminoglycosides or both has been reported. Therefore, we studied in vitro release from polymethylmethacrylate beads of antimicrobials with suitable spectra for orthopaedic infections, including cefazolin, ciprofloxacin, gatifloxacin, levofloxacin, linezolid, and rifampin (2.5%, 7.5%, and 15%). Beads were placed in a continuous flow chamber, and antimicrobial concentrations in chamber outflow were determined by bioassay at timed intervals thereafter. Release profiles were bimodal with initial rapid release of high concentrations followed by sustained, slow release. Antimicrobial agents studied showed varied release profiles, indicating that elution from polymethylmethacrylate is unique to individual antimicrobial agents. Increasing antimicrobial concentration in polymethylmethacrylate increased peak concentrations and area under the curve. Cefazolin, ciprofloxacin, gatifloxacin, levofloxacin, linezolid, and rifampin may be suitable for incorporation into polymethylmethacrylate for management of orthopaedic infections.