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.     

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.     

The effect of glycine filler on the elution rate of gentamicin from acrylic bone cement: a pilot study

Elution of antibiotics from acrylic bone cement (polymethylmethacrylate [PMMA]) is dependent on the access of fluid to the depths of the cement that contains the antibiotic. Commercially prepared antibiotic beads that are porous have higher elution rates than hand-mixed, nonporous antibiotic PMMA mixtures. To increase the elution of gentamicin from hand-mixed PMMA, glycine was added as a filler to produce porosity. Elution of gentamicin from the antibiotic PMMA-glycine mixture increased with increasing amounts of glycine. With 3.6 g gentamicin powder and 14 g of crystalline glycine per batch of Palacos PMMA, the elution of gentamicin from the PMMA at 2 days was, similar to the previously documented elution of gentamicin from commercially prepared porous Septopal PMMA beads. With further investigation it may be possible to identify a specific filler and a volume of filler that can be hand mixed in antibiotic PMMA to produce the elution behavior that is needed for specific clinical requirements.     

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.     

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.     

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.     

Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements

The use of antibiotic-loaded bone cement is an accepted treatment method for infected joint arthroplasties. It is helpful to separate the use of antibiotic-loaded bone cement as a method of prophylaxis as compared with the treatment of an established infection. A low dose of antibiotic-loaded bone cement (< or = 1 g of antibiotic per batch of cement) should be used for prophylaxis, and high-dose antibiotic-loaded bone cement (> 1 g antibiotic per batch of cement) is indicated for treatment. The only commercially available antibiotic-loaded bone cement products are low dose, with the use of tobramycin or gentamicin as an antibiotic selection. High-dose antibiotic-loaded bone cement requires hand mixing by the surgeon to facilitate the use of high dosages and choices of multiple antibiotics. Treatment of infected hip and knee arthroplasties with high-dose antibiotic-loaded bone cement is aided by the use of spacers of various shapes and sizes. These spacers, whether they are static or articulating (mobile), are meant to provide local delivery of antibiotics, stabilization of soft tissues, facilitation of an easier reimplantation, and improved clinical outcomes.     

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 Palaes R was evaluated in vitro. Four other bone cements were included in this ttudy 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 1.8μg/ml) and urine. However, in wound exudate, derived directly from the vicinity of the implanted cement, gentamicin concentrations up to 150μg/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).     

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 Palaes R was evaluated in vitro. Four other bone cements were included in this ttudy 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 1.8μg/ml) and urine. However, in wound exudate, derived directly from the vicinity of the implanted cement, gentamicin concentrations up to 150μg/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).     

Antibiotic-loaded bone cement for infection prophylaxis in total joint replacement

Use of antibiotic-loaded bone cement for prophylaxis against infection is not indicated for patients not at high risk for infection who are undergoing routine primary or revision joint replacement with cement. The mechanical and elution properties of commercially available premixed antibiotic-loaded bone-cement products are superior to those of hand-mixed preparations. Use of commercially available antibiotic-loaded bone-cement products has been cleared by the United States Food and Drug Administration only for use in the second stage of a two-stage total joint revision following removal of the original prosthesis and elimination of active periprosthetic infection. Use of antibiotic-loaded bone cement for prophylaxis against infection in the second stage of a two-stage total joint revision involves low doses of antibiotics. Active infection cannot be treated with commercially available antibiotic-loaded bone cement as such treatment requires higher doses of antibiotics.     

Addition of hand-blended generic tobramycin in bone cement: effect on mechanical strength

This study compared the mechanical strength of commercially prepared antibiotic bone cement (Simplex With Tobramycin; Stryker, Mahwah, NJ), cement with generic tobramycin (Pharma-Tek, Huntington, NY) blended in by the orthopedic nursing staff, and standard nonantibiotic bone cement. The results showed an approximate 36% decrease in the strength of the cement with hand-mixed generic tobramycin, while the commercial antibiotic cement remained unchanged relative to the nonantibiotic control. These results indicate the mechanical properties of bone cement can be severely compromised by hand-mixing antibiotics into bone cement at the time of surgery.     

Hand-mixed and Premixed Antibiotic-loaded Bone Cement Have Similar Homogeneity

Since low-dose antibiotic-loaded bone cement (ALBC) was approved by the FDA for second-stage reimplantation after infected arthroplasties in 2003, commercially premixed low-dose ALBC has become available in the United States. However, surgeons continue to mix ALBC by hand. We presumed hand-mixed ALBC was not as homogeneous as commercially premixed ALBC. We assessed homogeneity by determining the variation in antibiotic elution by location in a batch, from premixed and hand-mixed formulations of low-dose ALBC. Four hand-mixed methodologies were used: (1) suspension—antibiotic powder in the liquid monomer; (2) no-mix—antibiotic powder added but not mixed with the polymer powder before adding monomer; (3) hand-stirred—antibiotic powder stirred into the polymer powder before the monomer was added; and (4) bowl-mix—antibiotic powder mixed into polymer powder using a commercial mixing bowl before the monomer was added. Antibiotic elution was measured using the Kirby-Bauer bioassay. None of the mixing methods had consistently dissimilar homogeneity of antibiotic distribution from the others. Based upon our data we conclude hand-mixed low-dose ALBC is not less homogeneous than commercially premixed formulations. This work was supported by a grant from OREF and funds from Banner Health. Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. This work was performed at Arizona State University, Phoenix, AZ.     

In-vitro-Freisetzung von Antibiotika aus SmartSet HV- und Palacos R-Knochenzement und deren Einfluss auf die mechanischen Eigenschaften

BACKGROUND: The continuing emergence of new bone cements with additional antibiotics makes it important to establish which one will provide the most favourable antibiotic elution. An in vitro antibiotic elution and mechanical study was therefore carried out to compare a newer bone cement, SmartSet, with the established Palacos R cement. METHODS: Samples were prepared with each cement adding 1 g gentamicin, 1 g of vancomycin, or 1 g of gentamicin and vancomycin. The samples were analysed using fluorescence polarisation immunoassay. Mechanical tests were performed to determine whether any significant degradation in the cement strength occurred following addition of the antibiotic. RESULTS: With regards to gentamicin release Palacos R eluted significantly more antibiotic over the study period than SmartSet (p<0.001). Both cements eluted significantly more gentamicin when two antibiotics were added. With respect to vancomycin release there was no significant difference. Palacos R was significantly stronger than SmartSet in the 4-point bending test when the gentamicin + vancomycin antibiotic groups were compared (p=0.01). Palacos R also demonstrated a higher elastic modulus than SmartSet when the gentamicin and gentamicin + vancomycin groups were compared (p=0.03, p=0.005). CONCLUSIONS: Gentamcin shows better release characteristics from Palacos R. Both cements exhibited synergistic release of combined antibiotics.     

Copal Bone Cement Is More Effective in Preventing Biofilm Formation than Palacos R-G

Bone cements loaded with combinations of antibiotics are assumed more effective in preventing infection than bone cements with gentamicin as a single drug. Moreover, loading with an additional antibiotic may increase interconnectivity between antibiotic particles to enhance release. We hypothesize addition of clindamycin to a gentamicin-loaded cement yields higher antibiotic release and causes larger inhibition zones against clinical isolates grown on agar and stronger biofilm inhibition. Antibiotic release after 672 hours from Copal bone cement was more extensive (65% of the clindamycin and 41% of the gentamicin incorporated) than from Palacos R-G (4% of the gentamicin incorporated). The higher antibiotic release from Copal resulted in a stronger and more prolonged inhibition of bacterial growth on agar. Bacterial colony counting and confocal laser scanning microscopy of biofilms grown on the bone cements suggest antibiotic release reduced bacterial viability, most notably close to the cement surface. The gentamicin-sensitive Staphylococcus aureus formed gentamicin-resistant small colony variants on Palacos R-G and therefore Copal more effectively decreased biofilm formation than Palacos R-G. Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.     

Antibacterial efficacy of a new gentamicin‐coating for cementless prostheses compared to gentamicin‐loaded bone cement

Cementless prostheses are increasingly popular but require alternative prophylactic measures than the use of antibiotic‐loaded bone cements. Here, we determine the 24‐h growth inhibition of gentamicin‐releasing coatings from grit‐blasted and porous‐coated titanium alloys, and compare their antibacterial efficacies and gentamicin release‐profiles to those of a commercially available gentamicin‐loaded bone cement. Antibacterial efficacy increased with increasing doses of gentamicin in the coating and loading with 1.0 and 0.1 mg gentamicin/cm² on both grit‐blasted and porous‐coated samples yielded comparable efficacy to gentamicin‐loaded bone cement. The coating had a higher burst release than bone cement, and also inhibited growth of gentamicin‐resistant strains. Antibacterial efficacy of the gentamicin coatings disappeared after 4 days, while gentamicin‐loaded bone cement exhibited efficacy over at least 7 days. Shut‐down after 4 days of gentamicin‐release from coatings is advantageous over the low‐dosage tail‐release from bone cements, as it minimizing risk of inducing antibiotic‐resistant strains. Both gentamicin‐loaded cement discs and gentamicin‐coated titanium coupons were able to kill gentamicin‐sensitive and ‐resistant bacteria in a simulated prothesis‐related interfacial gap. In conclusion, the gentamicin coating provided similar antibacterial properties to those seen by gentamicin‐loaded bone cement, implying protection of a prosthesis from being colonized by peri‐operatively introduced bacteria in cementless total joint arthroplasty. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1654–1661, 2011     

A biodegradable antibiotic delivery system based on poly-(trimethylene carbonate) for the treatment of osteomyelitis

Background and purpose Many investigations on biodegradable materials acting as an antibiotic carrier for local drug delivery are based on poly(lactide). However, the use of poly(lactide) implants in bone has been disputed because of poor bone regeneration at the site of implantation. Poly(trimethylene carbonate) (PTMC) is an enzymatically degradable polymer that does not produce acidic degradation products. We explored the suitability of PTMC as an antibiotic releasing polymer for the local treatment of osteomyelitis.Methods This study addressed 2 separate attributes of PTMC: (1) the release kinetics of gentamicin-loaded PTMC and (2) its behavior in inhibiting biofilm formation. Both of these characteristics were compared with those of commercially available gentamicin-loaded poly(methylmethacrylate) (PMMA) beads, which are commonly used in the local treatment of osteomyelitis.Results In a lipase solution that mimics the in vivo situation, PTMC discs with gentamicin incorporated were degraded by surface erosion and released 60% of the gentamicin within 14 days. This is similar to the gentamicin release from clinically used PMMA beads. Moreover, biofilm formation by Staphylococcus aureus was inhibited by approximately 80% over at least 14 days in the presence of gentamicin-loaded PTMC discs. This is similar to the effect of gentamicin-loaded PMMA beads. In the absence of the lipase, surface erosion of PTMC discs did not occur and gentamicin release and biofilm inhibition were limited.Interpretation Since gentamicin-loaded PTMC discs show antibiotic release characteristics and biofilm inhibition characteristics similar to those of gentamicin-loaded PMMA beads, PTMC appears to be a promising biodegradable carrier in the local treatment of osteomyelitis.     

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.     

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.     

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.     

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.