The elution of colistimethate sodium from polymethylmethacrylate and calcium phosphate cement beads

Gram-negative bacilli resistance to all antibiotics, except for colistimethate sodium (CMS), is an emerging healthcare concern. Incorporating CMS into orthopedic cement to treat bone and soft-tissue infections due to these bacteria is attractive, but the data regarding the elution of CMS from cement are conflicting. The in vitro analysis of the elution of CMS from polymethylmethacrylate (PMMA) and calcium phosphate (CP) cement beads is reported. PMMA and CP beads containing CMS were incubated in phosphate-buffered saline and the eluate sampled at sequential time points. The inhibition of the growth of a strain of Acinetobacter baumannii complex by the eluate was measured by disk diffusion and microbroth dilution assays, and the presence of CMS in the eluate was measured by mass spectroscopy. Bacterial growth was inhibited by the eluate from both PMMA and CP beads. Mass spectroscopy demonstrated greater elution of CMS from CP beads than PMMA beads. The dose of CMS in PMMA beads was limited by failure of bead integrity. CMS elutes from both CP and PMMA beads in amounts sufficient to inhibit bacterial growth in vitro. The clinical implications of these findings require further study.     

Determining potential of PMMA as a depot for rifampin to treat recalcitrant orthopaedic infections

BackgroundOpen fractures are often complicated by infection. In cases of severe soft tissue and vascular injury, systemic antibiotics may be ineffective due to their inability to reach and provide direct antimicrobial activity to the zone of injury. High antibiotic concentrations within the wound can be achieved with reduced systemic toxicity by using local antibiotic delivery. As bacteria associated with musculoskeletal injuries frequently form biofilms, antibiotic selection is important. Herein, the use of rifampin, an antibiotic with activity against biofilms, delivered via polymethylmethacrylate (PMMA) beads is evaluated for use in a traumatic musculoskeletal wound model.MethodsPMMA beads loaded with rifampin, or combinations of rifampin and vancomycin, were prepared and evaluated for time to curing, drug release kinetics in vitro, and infection prevention in vivo using a well-established rat model of musculoskeletal infection. A segmental bone defect was created and contaminated with methicillin susceptible Staphylococcus aureus (UAMS-1). Wounds were debrided, irrigated, and treated with PMMA beads, containing rifampin or combinations of rifampin plus vancomycin, following a 6-h (early) or 24-h (delayed) treatment. After 14 days, tissue, implants, and beads were removed for bacterial quantification and assessed for rifampin resistance.ResultsThere was a direct association between loaded concentration and release kinetics of the rifampin and vancomycin from PMMA beads. Higher rifampin concentrations delayed PMMA curing times. The addition of vancomycin to PMMA resulted in more rapid release of rifampin from beads. However, the highest concentration of rifampin loaded PMMA beads (10% wt/wt) was the only treatment to significantly reduce bacterial counts. No rifampin resistance was observed.ConclusionAlthough higher concentrations of rifampin resulted in significant reductions of bacteria, these levels extended PMMA curing times and transformed PMMA material characteristics. While these characteristics make the material unsuitable for weight-bearing applications, such as total joint arthroplasty, the use of rifampin-loaded PMMA beads may be an effective intervention in a contaminated traumatic extremity wound due to its ability to eradicate biofilms.     

Comparative evaluation of the diffusion of tobramycin and cefotaxime out of antibiotic-impregnated polymethylmethacrylate beads

Both tobramycin and cefotaxime diffuse from antibiotic-impregnated polymethylmethacrylate (PMMA) beads in quantities sufficient to inhibit the growth of bacteria on agar lawns or in broth cultures over a 28-day period. Extraction of antibiotic from tobramycin or cefotaxime-impregnated PMMA beads revealed that substantial amounts of both antibiotics remained within the beads despite 28 days of diffusion. Diffusion of antibiotic from the PMMA beads during the initial 3-5 days is much greater than occurs for the remainder of the 4-week period. The results of the study suggest that perhaps tobramycin of cefotaxime-impregnated PMMA beads would produce local levels of antibiotic high enough to sterilize a given dead space for a period of 28 days.     

Elution of vancomycin, daptomycin, and amikacin from acrylic bone cement.

Increasing antibiotic resistance of bacteria that infect prosthetic joints has stimulated interest in the incorporation of more effective antimicrobial agents into polymethylmethacrylate (PMMA). Vancomycin and daptomycin are effective against nearly all staphylococci and streptococci, and amikacin has a broader spectrum against gram-negative bacilli than do other aminoglycosides such as gentamicin. These three antibiotics maintained bioactivity after incorporation into several commonly used preparations of PMMA and eluted readily into the surrounding medium. Preparing PMMA under negative atmospheric pressure, which decreases porosity, caused a 50% reduction in antibiotic release; the addition of 25% dextran, which increases porosity, greatly facilitated elution of these antibiotics. Based on their broad antibacterial effect against gram-positive and gram-negative bacteria, inclusion of vancomycin and amikacin in PMMA merits clinical study. The addition of these antibiotics to PMMA, together with dextran, may be applicable when structural integrity is unimportant but a substantial local antimicrobial effect is desired, such as in the use of antibiotic-containing beads to treat osteomyelitis.     

In vitro characteristics of tobramycin-PMMA beads: compressive strength and leaching

Antibiotic-impregnated polymethylmethacrylate (PMMA) bone cement beads have been used as a local drug delivery system for the treatment of bone and soft tissue infections. The beads deliver a high local level of antibiotic with a decreased risk of toxic systemic levels. This study was undertaken to determine the antibiotic release characteristics of tobramycin-impregnated beads over time and to determine the compressive strength of these beads. Acrylic resin (PMMA) bone cement beads were prepared with three different concentrations of tobramycin. The beads were tested for compressive strength, and their antibiotic release characteristics were determined over a 21 day period by radioimmunoassay and by biological testing against a variety of bacteria. The compressive strength of the beads was found to be adequate to avoid fragmentation during their clinical use. There was gradual release of tobramycin from the beads over the entire 21 days, but the release was most marked during the first 48 hours. There was antibiotic activity against both gram-negative and gram-positive organisms, except Enterococcus, for the entire 21 day period. The release of tobramycin followed a curvilinear relationship and was directly related to the initial antibiotic concentration of the bead. Tobramycin-impregnated polymethylmethacrylate beads may represent a reliable method of local antibiotic delivery with sustained activity against a broad spectrum of organisms.     

In vitro elution of ciprofloxacin from polymethylmethacrylate cement beads

The use of antibiotic-impregnated polymethylmethacrylate (PMMA) cement beads for the local delivery of antibiotics in the treatment of chronic osteomyelitis has become a standard orthopaedic practice. The increasing resistance to antibiotics of organisms associated with orthopaedic infections has led to interest in the incorporation of more effective antibiotics into PMMA cement. Ciprofloxacin, a synthetic fluoroquinolone, is potent against a broad spectrum of bacteria associated with osteomyelitis. In this study, strands of ciprofloxacin-impregnated PMMA cement beads were prepared with 0.2, 0.5, or 1.0 g of ciprofloxacin per 40 g of PMMA. The elution concentration of ciprofloxacin was at least 1–2 mcg/ml for 7 days (0.2 g), 30 days (0.5 g), and 42 days (1.0 g). This concentration is equivalent to the minimum inhibitory concentration for the common pathogens associated with osteomyelitis. Concurrent systemic and local ciprofloxacin therapy appears to be a method for the treatment of chronic osteomyelitis.     

In vitro elution of tobramycin from bioabsorbable polycaprolactone beads

OBJECTIVES: To compare the in vitro elution characteristics of tobramycin impregnated beads made of polycaprolactone (PCL) and polymethylmethacrylate (PMMA). DESIGN: Six-millimeter PCL and PMMA beads with 6% tobramycin were formed and placed in phosphate-buffered saline or newborn calf serum and incubated at room temperature or 37 degrees C. Aliquots were taken at intervals for eight weeks. Tobramycin levels were determined by fluorescent assay and antibacterial efficacy was assessed by measuring the zones of inhibition against Staphylococcus aureus and Pseudomonas aeruginosa on agar diffusion plates. RESULTS: Tobramycin elution rates at room temperature were similar up to three weeks. At three weeks, elution rates from PCL beads were twice those from PMMA beads, and at eight weeks, elution from PCL was quadruple that from PMMA. At 37 degrees C, tobramycin elution rates from PCL were eight times greater than those from PMMA by eight weeks. Total tobramycin eluted from PCL beads was 38.9% and 20% in PMMA beads. All samples showed bacteriostatic activity against S. aureus and P. aeruginosa at eight weeks. CONCLUSIONS: These in vitro results show that PCL has superior antibiotic elution characteristics compared with PMMA, and this may translate into a more effective antibiotic delivery vehicle. In addition, PCL is a bioabsorbable polymer, which may decrease the need for a second surgical procedure to remove retained beads.     

Antibiotic beads in the treatment of diabetic pedal osteomyelitis.

Antibiotic-impregnated polymethylmethacrylate (PMMA) beads have improved the outcome of osteomyelitis treatment in both experimental models and clinical trials. The primary benefit of antibiotic-impregnated PMMA beads is that they provide high local concentrations of antibiotic while systemic levels of antibiotic remain low. Little has been written about the specific use of antibiotic-impregnated PMMA beads in the treatment of diabetic pedal osteomyelitis. The authors review antibiotic-impregnated PMMA beads and provide examples of their use in the treatment of diabetic pedal osteomyelitis.     

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.     

Experimental and pharmacokinetic studies with gentamicin PMMA beads (author's transl)]

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.     

Rapid release of gentamicin from collagen sponge. In vitro comparison with plastic beads

The gentamicin-containing collagen sponge is a new product intended for local application in bone and soft-tissue infections. The release of gentamicin from the collagen sponges was compared in vitro to that from polymethyl-methacrylate (PMMA) beads. A static and kinetic experimental design was used. In the static model, pieces of collagen sponge or PMMA beads were added to 20 mL of distilled water, and during the following hours the gentamicin concentrations in the water were repeatedly measured. This simple model was extended to the kinetic model as the released gentamicin was removed from the water exponentially by means of an infusion-withdrawal pump. The gentamicin was released from the carrier substances with increasing half lives. During the first 4 hours, the half life increased from 0.2 to 1.5 hours for the collagen sponge and from 3 to 78 hours for the PMMA beads. After 1.5 hours, 95 percent of the gentamicin was released from the sponges, whereas only 8 percent was released from the beads.     

Rapid release of gentamicin from collagen sponge: In vitro comparison with plastic beads

The gentamicin-containing collagen sponge is a new product intended for local application in bone and soft-tissue infections. The release of gentamicin from the collagen sponges was compared in vitro to that from polymethyl-methacrylate (PMMA) beads. A static and kinetic experimental design was used. In the static model, pieces of collagen sponge or PMMA beads were added to 20 mL of distilled water, and during the following hours the gentamicin concentrations in the water were repeatedly measured. This simple model was extended to the kinetic model as the released gentamicin was removed from the water exponentially by means of an infusion-withdrawal pump. The gentamicin was released from the carrier substances with increasing half lives. During the first 4 hours, the half life increased from 0.2 to 1.5 hours for the collagen sponge and from 3 to 78 hours for the PMMA beads. After 1.5 hours, 95 percent of the gentamicin was released from the sponges, whereas only 8 percent was released from the beads.     

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.     

MRSA-Infektionen des Bewegungsapparats

INTRODUCTION: We present gentamicin-vancomycin-impregnated beads that can be produced intraoperatively in moulds and demonstrated their successful use in ten cases of problematic Methicillin-resistant Staphylococcus aureus (MRSA) infection. METHODS: To produce the antibiotically loaded PMMA beads, a two-part mould of polyoxymethylene was used. The mixture of PMMA and antibiotic is poured into the mould halves, and during polymerisation the halves bond together. The in vivo antibiotic concentrations of wound secretion from the redon drainage were measured by fluorescence-polarisation immunoassay, and a concentration/time function was determined. The PMMA beads (2 g of vancomycin plus 0.5 g of gentamicin plus 40 g of PMMA) were implanted in ten patients aged 41-76 years. RESULTS: In all ten patients, the infection was cured (follow-up 15 months). CONCLUSION: The combination of gentamicin and vancomycin in the PMMA of standardised beads represents a good alternative in the treatment of MRSA infections. Understanding of the mechanism of antibiotic release from PMMA allows differentiated dosing during systemic application.     

Wound and serum levels of tobramycin with the prophylactic use of tobramycin-impregnated polymethylmethacrylate beads in compound fractures

Antibiotic-impregnated polymethylmethacrylate (PMMA) beads have been useful in treating orthopedic infections. Local delivery has been reported to establish wound antibiotic levels well above the therapeutic range while avoiding serum levels associated with increased incidence of side effects. After operative debridement, 70 patients with compound fractures were treated prophylactically with tobramycin-impregnated PMMA beads. Observations of antibiotic levels in 27 patients demonstrated antibiotic levels in the wound drainage and clot that were significantly in excess of the usual therapeutic range for tobramycin and simultaneous nontoxic serum levels. Significant levels of tobramycin can be achieved in the extracellular fluid at the fracture site when tobramycin-impregnated PMMA beads are placed in the wound after irrigation and debridement.     

Noncommercial fabrication of antibiotic-impregnated polymethylmethacrylate beads. Technical note

Antibiotic-impregnated polymethylmethacrylate (PMMA) beads were fabricated by means of injections in specially designed molds to produce small and large beads. In vitro concentrates from these beads for 30 days were found to release tobramycin in an exponential function.     

The release of Gentamycin into the wound secretions from polymethylmethacrylate beads

Summary Following implantation of Gentamycin PMMA beads, the concentration of antibiotics in the wound secretion was investigated in an animal experiment which corresponded to the clinically applied procedure.The measured concentrations of active substance over a period of 6 days were on an average 8 times higher than the maximum serum titers obtainable with systemic application of antibiotics, and consequently they exceeded by several dilution stages the minimum bactericidal concentrations of most of those bacteria which are responsible for infections of wounds and bones. The kinetics of release of Gentamycin out of the PMMA beads are presented, and compared with that of bone cement which contains antibiotics and which is used in endoprostheses. From the results, conclusions about the intraoperative techniques which should be realised have been drawn, conditions which are of decisive importance for the success of this new treatment for infections of the bone and soft tissue.

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Zusammenfassung Die Antibiotika-Konzentration im Wundsekret nach Implantation von Gentamycin-PMMA-Kugelketten wurden in einem tierexperimentellen Modell, das dem klinisch angewandten Verfahren entspricht, untersucht.Die gefundenen Wirkstoff-Konzentrationen lagen im Mittel 6 Tage lang 8mal höher als die bei systemischer Antibiotika-Applikation erreichbaren maximalen Serum-Titer und überschritten damit die minimalen bakteriziden Konzentrationen der meisten für Wund- und Knocheninfektionen verantwortlichen Bakterien um mehrere Verdünnungsstufen. Dargestellt wird die Freisetzungskinetik des Gentamycins aus den PMMA-Kugeln und mit den Verhältnissen bei Antibiotika-enthaltendem Knochenzement verglichen, wie er bei der Endoprothetik eingesetzt wird. Aus den Ergebnissen sind die intraoperativ zu schaffenden Bedingungen abgeleitet, die für den Erfolg dieses neuen Behandlungsverfahrens bei Knochen- und Weichteil-Infektionen von entscheidender Bedeutung sind.

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Gentamycin PMMA Beads manufactured by E. Merck, Darmstadt     

The morphology of polymethylmethacrylate (PMMA) bone cement: surface structures and causes of their origin

This study deals with the correlation between the polymerizing bone cement and the surrounding tissue. The surface structures of bone cements, polymerized in air, in tissue medium (in vitro) and in human bone during implantation were investigated and compared with the contours of the tissue of the implant bed. Basing on the dimensional differences it was differentiated between contours of 1st order and 2nd order: contours of 1st order are within the macroscopic range, contours of 2nd order within the microscopic range. The surface of bone cement polymerized in living human tissue differed essentially from samples polymerized under laboratory conditions. The differences are to be seen macroscopically in the coarse relief as well as microscopically in the shape and the connection of the superficial methylmethacrylate beads. Bone cements, polymerized in air show an ideal, even and closed surface. Bone cements, polymerized in tissue medium exhibit macroscopically some wrinkles, in the microscopic range their contours are either closed (samples prepolymerized at 22 degrees C) or partly open and partly closed (samples prepolymerized at 24 degrees C). The surface of bone cement implants, retrieved from human bones are characterized macroscopically by a marked wrinkled and papillary relief, microscopically by flattened beads, and most often by an irregular, rough and open surface with isolated beads giving almost the impression of a porous surface structure. The character of the surface of the bone cement originates from external, mechanical influences, from changes in the volume of the bone cement and from effects of the surrounding tissues. The surface of the bone cement implanted in human bone conforms exactly with the contour of the adjacent tissue; the tissue contour is infact a negative of the cement surface. The incomplete connection between the superficial PMMA beads seems to be of some practical value: In areas, where the PMMA beads are largely isolated, the mechanical stressability of the "polymer composite" is relatively low. Under high load, beads and bead-clusters may break off the surface. Shattering of bone cement implants possibly may start from such an open, porous surface area where PMMA beads are extensive isolated.     

Successful treatment of empyema thoracis with polymethylmethacrylate antibiotic-impregnated beads in the guinea pig

Two hundred nine Duncan-Harley guinea pigs had intrathoracic inoculation with 10(8) Staphylococcus aureus, accompanied by blood and umbilical tape. One hundred fifty-two animals were excluded because of clinical recovery, early death, or complications related to intrathoracic polymethylmethacrylate (PMMA) bead placement. The remaining 57 animals had clinical signs of empyema thoracis and were the subjects of this study. Group I animals (N = 24) served as the controls and had no therapy. Group II animals (N = 14) were treated by intrathoracic placement of placebo PMMA beads. Group III animals (N = 19) were treated by intrathoracic placement of tobramycin sulfate-impregnated PMMA beads. There were no differences between the groups in pleural reaction or pneumonia scores. These findings demonstrate a similar host response to the established infection. Group III, however, had a higher sterilization rate than Groups I and II (p less than 0.05), a finding underlining the therapeutic effect of tobramycin-treated PMMA beads. We conclude that intrathoracic local antimicrobial therapy with slow-release tobramycin-impregnated PMMA beads may enhance empyema treatment by increasing the rate of local sterilization. More experiments are necessary to assess the efficacy of this potentially important therapeutic arm for the treatment of thoracic empyema.     

Use of antibiotic-loaded polymethylmethacrylate beads for the treatment of extracavitary prosthetic vascular graft infections

PURPOSE: This study was conducted to assess the efficacy of antibiotic-loaded polymethylmethacrylate (PMMA) beads in the management of lower extremity extracavitary prosthetic arterial graft infection. METHODS: This was a retrospective review of 34 patients treated for vascular surgical site (VSS) infections involving 36 prosthetic lower extremity arterial bypasses using antibiotic-loaded PMMA beads and culture-specific parenteral antibiotics for 4 to 6 weeks. Sites of graft infection were explored, debrided, and cultured. As determined from the results of Gram's stains of VSS purulence, PMMA powder was polymerized with an antibiotic (vancomycin, daptomycin, or tobramycin/gentamicin, or a combination), molded into a chain of beads, and implanted adjacent to the infected graft after debridement and pulsed-spray antibacterial lavage. All wounds were closed primarily with planned exploration to verify sterilization before a graft preservation or in situ replacement procedure. Treatment outcomes, including wound sterilization, were analyzed based on tissue culture isolates, procedures for persistent infection, and freedom from graft infection. RESULTS: Cultures isolated 42 pathogens, (32 gram-positive, 9 gram-negative, 1 Candida albicans) with methicillin-resistant Staphylococcus aureus (MRSA) cultured from 16 (44%) of 36 surgical site infections. As determined from the initial operative Gram's stain or a prior culture result, vancomycin PMMA beads were implanted in 29 of 36 VSS infections at the first procedure; daptomycin (n = 4) or tobramycin (n = 3) beads were implanted in the rest. Repeat VSS exploration and culture results led to an average of 2.5 antibiotic bead replacements before definitive treatment. A sterile (no growth on tissue culture) VSS was achieved in 87% of cases before a graft preservation (n = 16) or in-situ replacement of an infected graft (n = 20) procedure. No patient deaths occurred. Early and late limb salvage was 100%. Infection recurred in 4 (11%) VSSs during a mean 23-month follow-up period, one within 3 months owing to unrecognized bowel injury associated with in situ replacement of an aortofemoral graft limb. CONCLUSION: Antibiotic-loaded PMMA beads may be a useful adjunct in the contemporary surgical management of VSS infection involving a prosthetic graft. Wound sterilization was achieved in most VSSs before graft preservation or an in-situ replacement procedure, including infections caused by MRSA, a pathogen isolated in half of the extracavitary prosthetic graft infections. This preliminary trial shows the potential benefit of this new technique, but further study is required to prove efficacy.