ARTHROPLASTY
The cement spacer with multiple indentations INCREASING ANTIBIOTIC ELUTION USING A CEMENT SPACER ‘TEABAG’ S. Salih, A. Paskins, T. Nichol, T. Smith, A. Hamer From Northern General Hospital, Sheffield, United Kingdom
S. Salih, MA, MRCS, MD, Orthopaedic Registrar, A. Hamer, MD FRCS(Orth), Consultant Orthopaedic Surgeon, Department of Trauma and Orthopaedics Sheffield Teaching Hospitals NHS Foundation Trust, Herries Road, Sheffield S5 7AU, UK. A. Paskins, MRes, BSc (Hons), PhD Student, City Campus T. Nichol, BSc (Hons) MSc, PhD, Lecturer in Microbiology, City Campus T. Smith, MA, PhD, Professor of Microbiology, City Campus Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK. Correspondence should be sent to Mr S. Salih; e-mail: [email protected] ©2015 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620X.97B11. 35618 $2.00 Bone Joint J 2015;97-B:1519–24. Received 9 December 2014; Accepted after revision 2 July 2015
We investigated whether the indentation of bone cement spacers used in revision of infected joint arthroplasty with a MacDonald dissector increased the elution of antibiotic in vitro. A total of 24 cement discs containing either 0.17 g (0.88% w/w), 0.25 g (1.41% w/w), or 0.33 g (1.75% w/w) gentamicin of constant size were made. Of these, 12 were indented with the dissector. Each disc was immersed in ammonium acetate buffer in a sealed container, and fluid from each container was sampled at zero, one, three, six, 24, 48 and 72 hours and at one, and two weeks. The concentration of gentamicin in the fluid was analysed using high performance liquid chromatography mass spectrometry. The fluid sampled at 72 hours from the indented discs containing 0.17 g gentamicin (0.88% w/w) contained a mean of 113 mcg/ml (90.12 to 143.5) compared with 44.5 mcg/ml (44.02 to 44.90) in the fluid sampled from the plain discs (p = 0.012). In discs containing 0.33 g gentamicin (1.75% w/w), the concentration eluted from the indented discs at 72 hours was a mean of 316 mcg/ml (223 to 421) compared with a mean of 118 mcg/ml (100 to 140) from the plain discs (p < 0.001). At two weeks, these significant differences persisted. At nine weeks the indented discs eluted a greater concentration for all gentamicin doses, but the difference was only significant for the discs containing 0.17 g (0.88% w/w, p = 0.006). However if the area under the curve is taken as a measure of the total antibiotic eluted, the indented discs eluted more gentamicin than the plain discs for the 0.17 g (0.88% w/w, p = 0.031), the 0.25 g (1.41% w/w, p < 0.001) and the 0.33 g (1.75% w/w, p < 0.001) discs. When preparing antibiotic spacers for use in staged revision arthroplasty surgery we recommend indenting the spacer with a MacDonald dissector to increase the elution of antibiotic. Cite this article: Bone Joint J 2015;97-B:1519–24.
The addition of antibiotics to bone cement was introduced by Bucholz and Engelbrecht1 in the 1970s. Bone cement is used in a variety of orthopaedic applications including the treatment of infections where it acts as a carrier for the delivery of antibiotic to bone and softtissue.2 An increasing number of joint arthroplasties are being undertaken. More than 180 000 hip and knee arthroplasties were recorded in the National Joint Registry in England, Wales and Northern Ireland for 2014.3 During the last eight years the number of staged revisions recorded for infection has increased from 954 (24% of revisions)4 to 1317 (23%) for knees,3 and 804 (12%)4 to 1249 (13%)3 for hips. Although the rate of revision has not changed, the number of staged revisions for infection has increased proportionally to the increased number of primary arthroplasties.3,4 During the first stage, the infected components are removed and an antibiotic loaded cement
VOL. 97-B, No. 11, NOVEMBER 2015
spacer is often inserted after thorough debridement.5 Many bone cements are available with antibiotics incorporated in the powder. Further antibiotic may be added to cement powder before mixing with the monomer to tailor the spectrum of activity of the antibiotics in the cement. This requires the antibiotic to be available as a powder and to be thermostable.2 Gentamicin,2,6 tobramycin7 and vancomycin8 have been successfully mixed with cement and eluted at clinically significant levels. Cement spacers for revision arthroplasty are commercially available, but we prefer to make spacers intra-operatively for individual application. These spacers may be articulated or surround a temporary arthrodesis nail. In either case the senior author's (AJH) practice has been to mould the spacer after mixing. As the cement is curing several indentations are made in the surface of the cement using a Mac1519
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Table I. Number of indentations in each indented disc
Disc 1 Disc 2 Disc 3
0.88% w/w vacuum mixed indented
0.88% w/w hand mixed indented
1.41% w/w hand mixed indented
1.75% w/w hand mixed indented
34 32 32
28 34 27
26 25 31
29 31 30
Donald dissector. This process creates an indented surface on the spacer that looks like a teabag, which we hypothesised may increase the elution of antibiotic by increasing the surface area of the spacer. The elution of antibiotics from cement spacers appears to be affected by porosity,6 surface area9 and mixing technique.10 The elution increases if the surface area of the spacer increases. This was demonstrated by Masri et al9 using a patterned mould contributing to the improvement of a commercially available articulating spacer (PROSTALAC, DePuy Synthes, Leeds, United Kingdom). To our knowledge, the technique of indenting cement after mixing has not previously been described, and whether this technique increases the elution of antibiotic has not been investigated. The purpose of this study was to test, in vitro, whether indenting the spacer with a MacDonald dissector increases the elution of gentamicin from bone cement.
Materials and Methods A polythylene and stainless steel mould was manufactured in the workshop at the host institution allowing the creation of six cement discs with a diameter of 4 cm and a thickness of 1.2 cm from a standard double mix of cement (2 × 40 g of pack size polymer powder and 2 × 20 ml of monomer liquid) with no waste of cement. Discs containing 0.17 g of gentamicin (0.88% w/w) were made using a double mix of Heraeus Palacos R+G cement (each containing 0.5 g of gentamicin, Heraeus Medical GmbH, Wehreim, Germany) resulting in a total of 1 g of gentamicin distributed between six discs. Discs containing 0.25 g of gentamicin (1.41% w/w) were made with one mix of Heraeus Palacos R+G (0.5 g of gentamicin) and one mix of Heraeus Copal G+C (containing 1 g of gentamicin) resulting in a total of 1.5 g of gentamicin distributed between six discs. Discs containing 0.33 g of gentamicin (1.75% w/w) were made with two mixes of Heraeus Copal G+C (each containing 1 g of gentamicin) resulting in 2 g of gentamicin distributed among six discs. It should be noted that Copal G+C also contains clindamycin but its presence was not analysed in the subsequent work. Cement was stored at room temperature for 24 hours before mixing and all the discs were mixed sequentially on the same day. Cement was mixed for 30 seconds according to the manufacturer's instructions. Hand-mixed discs were mixed, without vacuum extraction attached, in a Summit multi-axial bowl (Summit Medical, Bourton-on-the-Water, United Kingdom) and the vacuum mixed discs were prepared in a Cemvac vacuum mixing syringe (Cemvac System
AB, Linkoping, Sweden). The cement was placed into the mould during the early application or working time (between two and three and a half minutes after the initiation of mixing) to produce six discs. During the late application and early curing time (after four minutes) the upper surface of three of the discs was indented with a MacDonald dissector, while the remaining three discs in the mould were left plain. Indentation was performed as would be in vivo. There was no predetermined density of indentations, but indentations were placed on the surface of the cement spacer in a manner which maximised the number of indentations without deforming the shape of the spacer. Once fully cured, the discs were removed from the mould and allowed to cool overnight at room temperature. Thus, there were three discs of each type, and a total of 24 discs. The number of indentations per disc is summarised in Table I. The depth of the indentations was measured using the MacDonald blade, which is 5 mm wide. The mean depth was 10 mm (9.5 to 10.5). Thus, the internal dimensions of each indentation were 1 cm2. Each disc was then immersed in 150 mL of 0.1 M ammonium acetate buffer (pH 7.4) in a sealed jar and stored at room temperature. Using a Gilson pipette (Gilson Inc, Middleton, Wisconsin), 500 μL of the solution was removed after stirring, to ensure uniform antibiotic dispersal, at zero, one, three, six, 24, 48, 72, 168 hours (one week), 336 hours (two weeks), and 1512 hours (nine weeks). Samples were frozen at -20oC until the time of analysis. Analysis of the concentration of gentamicin in each sample was undertaken using high performance liquid chromatography – mass spectometry (HPLC-MS) as follows. A 100 μl sample of fluid from each soaking disc was loaded into 2 ml autosampler vials (National Scientific, Rockwood, Tennessee) containing 200 μl inserts (Chromacol, Welwyn Garden City, United Kingdom) and loaded into the autosampler. HPLC-MS was performed using a Luna 5u C18 (2) 100 A (150 mm × 1.0 mm, particle size 5 μm) column (Phenomenex, Torrance, California). The system consisted of two Perkin Elmer series 200 micropumps (Perkin Elmer Incorporated, Shelton, Connecticut) coupled with a Finnigan MAT LCQ mass spectrometer (Thermo Electron Corporation, San Jose, California), operated using Xcalibre software (Thermo Electron Corporation). The system was run isocratically, with a mobile phase consisting of 20% MeOH (80% ddH2O) with 0.1% trifluoroacetic acid, with an acquisition time of eight minutes, plus five minutes equilibration time at the beginning of each run. The rate of flow THE BONE & JOINT JOURNAL
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Table II. Table showing mass in grams of each disc
Disc 1 Disc 2 Disc 3 Mean
0.88% w/w vacuum mixed plain
0.88% w/w vacuum mixed indented
0.88% w/w hand mixed plain
0.88% w/w hand mixed indented
1.41% w/w hand mixed plain
1.41% w/w hand mixed indented
1.75% w/w Hand mixed plain
1.75% w/w Hand mixed indented
17.70 17.80 19.40 18.30
19.00 19.00 18.50 18.83
18.40 18.60 18.90 18.63
18.40 20.10 18.10 18.87
19.20 18.50 19.20 18.97
18.60 18.90 19.09 18.86
19.50 19.10 18.70 19.10
19.20 18.90 20.00 19.37
through the column was 0.05 ml/min and scans were carried out in positive ion mode with selected ion monitoring detection at 478 m/z (± 1.00), corresponding with the protonated gentamicin parent ion. The mass spectrometer was tuned to the mass of 478 m/z using the autotune function. Statistical analysis. Results were recorded in Excel 2010 (Microsoft, Redmond, Washington), and statistical analysis performed using SPSS v.17 software (IBM Corp., Armonk, New York) with graphs produced in Prism 5 (Graphpad Software, San Diego, California). Data were shown to be normally distributed using both quantile-quantile normality plots and Shapiro-Wilk normality testing. The means for each type of disc were taken and compared using a one way analysis of variance (ANOVA) with Bonferroni's Multiple Comparisons post-test to compare means between plain discs and indented discs for each concentration with the significance level set at a p-value of < 0.05.
Results The mass of each disc is shown in Table II. There was no significant difference in mass between the discs of the different groups. The indented discs had a mean of 30 (standard deviation 3; 26 to 34) indentations per disc (Table I). Gentamicin became detectable in most of the fluid at one hour, and significant differences in the concentration of gentamicin eluted were seen between the plain discs and the indented discs by 48 hours (Fig. 1). For example, at one week, the mean concentration of gentamicin in the eluted fluid from the indented 0.33 g discs (1.75% w/w) was 481.1 μg/mL (449.2 to 546.8) compared with a mean of 193.0 μg/mL (176.3 to 202.6) in the plain discs (p < 0.001, one-way ANOVA with Bonferroni post-test). At nine weeks the increased elution from the indented discs compared with the plain discs persisted. Although the differences in concentration of gentamicin detected at this stage was significant only for the difference between the plain and indented hand-mixed discs containing 0.17 g of gentamicin (0.88% w/w, p = 0.006, Fig. 2), the total elution of gentamicin measured as the area under the curve (AUC) was significantly greater for all the hand-mixed discs (Fig. 3). The hand-mixed discs containing 0.17 g (0.88% w/w), 0.25 g (1.41% w/w), and 0.33 g (1.75% w/w) of gentamicin had a greater AUC (and hence a greater elution of antibiotic) when compared with their corresponding plain discs (p = 0.031 for 0.17 g discs and < 0.001 for 0.25 g and 0.33 g disc comparisons, one-way ANOVA with Bonferroni posttest). Although a greater amount of gentamicin was eluted VOL. 97-B, No. 11, NOVEMBER 2015
from the 0.17 g of gentamicin-containing vacuum mixed indented discs than from the corresponding discs made from hand-mixed cement, this difference did not reach statistical significance (p = 0.381). The total amount of eluted gentamicin can be estimated by extrapolating from the concentration sampled at nine weeks. The solution was stirred before sampling to ensure an even distribution of gentamicin throughout the buffer. Gentamicin is stable for several months in solution.6 With these assumptions, between 80% and 90% of the total gentamicin in the discs was eluted by nine weeks in the handmixed indented spacers, whereas between 40% and 60% was eluted in the plain discs.
Discussion These findings support the indentation of cement spacers with a MacDonald dissector to increase the elution of gentamicin from commercially available gentamicin loaded cement. Both the concentration of eluted antibiotic and the total released over a nine-week period is greater when the spacer is indented for a given mass and volume of cement. This work does not suggest a particular density of indentations, neither does it propose a configuration for the indentations. It is estimated that there is an increase in surface area of 1 cm2 with each 'stab' of the MacDonald dissector. Given that there was a mean of 30 indentations (26 to 34) per cement disc, it is estimated that the surface area of each disc was increased by 75% using this technique. It may be possible to further increase the surface area by using another configuration such as a ‘+’-shaped indentation. This was not tested because, in the authors’ experience, the generation of more complex patterns is more time consuming and is limited by the curing time of the cement. A MacDonald dissector was used because of its ready availability on a standard instrument tray and it can produce clean simple indentations. There are commercially available antibiotic loaded cement spacers that make use of a textured surface to increase the surface area and antibiotic elution.9 The use of cement beads has shown the same increase in antibiotic elution with increased surface area.11 However, preparing cement spacers by hand is less expensive and allows an antibiotic bespoke spacer to be made for each case. In addition, the increase in the surface area to volume ratio is potentially much greater when indenting with a MacDonald dissector when compared with a 10% increase gained by creating a surface pattern for manufacturing purposes.9
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2400
0.25g D 0.25g
2000 Conc (μg/mL)
2000 Conc (µg/mL)
2400
0.17g D 0.17g 0.17g VAC D 0.17g VAC
1600 1200 800
1600 1200 800
*
400
** ***
400
0
***
***
0 0
50
100 150 200 250 300 350 400 Time (hrs)
0
1512
50
100 150 200 250 300 Time (hrs)
1512
Fig. 1b
Fig. 1a
2400
0.33g D 0.33g
2000
Conc (μg/mL)
350 400
1600 1200 ***
800
***
***
***
400 0 0
50
100 150 200 250 300 350 400 Time (hrs)
1512
Fig. 1c Graphs showing the mean concentration of gentamicin eluted by cement discs containing a) 0.17 g gentamicin (0.88% w/w); b) 0.25 g gentamicin (1.41% w/w); and c) 0.33 g gentamicin (1.75% w/w). Error bars represent standard deviations (n = 3).* p = 0.039; ** p = 0.003; *** p < 0.001; VAC, vacuum mixed disc; D, perforated disc.
The differences in the elution of gentamicin between the plain and indented discs were not statistically significant until 48 hours. This may be because the differences in concentration are small, and there is inherent variability in the HPLC-MS readings. However, by 48 hours there was a highly significant difference between the indented and plain 1.41% w/w (p < 0.001) and 1.75% w/w discs (p < 0.001). The spacers continued to elute antibiotic for at least nine weeks, similar to previous findings.9,12 Masri et al9 suggested that the difference between the textured and plain spacers was significant up to two weeks only. This may be accounted for by the rate of elution. It may be that the rate of elution is greater with a greater surface area. There is a finite amount of antibiotic that can be released from a spacer, and this may be the same for any given volume of antibiotic loaded cement. Given that the difference in surface area was only 10%, in the investigation by Masri et al9 the time taken for the plain disc to 'catch up' may have been only two weeks. In this study, indenting the spacer
increased the surface area of spacer by 75% and therefore, a longer period may be required before the plain discs would be shown to release a similar amount of antibiotic. However, given that a high peak dose is desired as quickly as possible for the best chance of eradicating microorganisms, indentation of the spacer is still desirable. At two weeks the elution of gentamicin from the handmixed indented discs was at least double that of the corresponding plain discs, suggesting that the increased elution of gentamicin was not purely a surface area phenomenon. The mechanism of antibiotic elution is debated. Early experiments with sodium chloride supported the theory that the release of antibiotic was a passive surface phenomenon, and that a greater surface area would increase elution.13 Others have suggested that diffusion of antibiotic may occur through the matrix of bone cement14 but it is more likely that this occurs because of a series of microscopic cracks and pores in the cement effectively increasing its surface area.6,15,16 Indenting the spacer with a dissector THE BONE & JOINT JOURNAL
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2500
Conc (∝g/mL)
2000 *
1500 1000
0.33g D
0.33g
0.25g D
0.25g
0.17g D
0.17g
0.17g VAC
0
0.17g VAC D
500
Fig. 2 Graph showing the mean concentration of gentamicin in eluent at nine weeks. Error bars represent standard deviations.* p < 0.006; VAC, Vacuum mixed disc; D, perforated disc; 0.17 g, 0.88% w/w disc; 0.25 g, 1.41% w/w disc; 0.33 g, 1.75% w/w disc.
2 × 106
AUC (µghrs)
† 1.5 × 106
† *
1 × 106
5 × 105
0.33g D
0.33 g
0.25g D
0.25 g
0.17g D
0.17 g
0.17g VAC D
0.17g VAC
0
Fig. 3 Graph showing the mean area under curve at nine weeks. Error bars represent standard deviations.* p = 0.031; † p < 0.001; VAC, Vacuum mixed disc; D, perforated disc; 0.17 g, 0.88% w/w disc; 0.25 g, 1.41% w/ w disc; 0.33 g, 1.75% w/w disc.
may increase the effective surface area by more than 75% if the indentations expose cracks and pits within the body of the spacer, which would otherwise have not been in contact with the surface. Although this may weaken the cement, the purpose of a cement spacer in surgery for prosthetic joint infection is to deliver antibiotic at a higher concentration to the local tissues than could be achieved by parenteral administration5,12 and to maintain soft-tissue tension and limb length,17,18 rather than to offer structural or loadbearing support. In most cases, spacers are temporary,5 and increased porosity has been shown not to affect a spacer's function adversely or to cause failure when used in a staged revision procedure.19 VOL. 97-B, No. 11, NOVEMBER 2015
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A limitation of this work is that only one antibiotic was assayed, however the purpose of this study was to determine whether indentation of a spacer with a MacDonald dissector would increase the elution of antibiotic compared with a plain spacer. Gentamicin is commonly added to commercially-prepared antibiotic-loaded bone cement.5,18 Furthermore, the elution of gentamicin from Palacos has been shown to be more consistent and greater than its elution from other brands.14,16,20 The elution of gentamicin in this study did not seem to be affected by the presence of clindamycin in the discs containing Copal cement, unlike other work in which the presence of several antibiotics in cement appeared to inhibit elution.21 Although there were only three discs per condition, the results were both statistically and clinically significant. The range of concentration in the indented discs reflects the variability in clinical practice. Access to the spacer in vivo may be limited by the local anatomy or the curing time and different spacers will have a different number of indentations. Ammonium acetate buffer rather than serum was used to allow the use of HPLC-MS to give quantitative results. Other studies have shown that the elution of antibiotic from cement into buffer is the same22 or less23 than that into serum. Much of the early work on antibiotic elution from cement used agar plate diffusion assays, where the cement disc or inhibition of bacterial growth by the eluent fluid on an agar plate is used to estimate the concentration of antibiotic which is released.2,6,21-23 Here, since two antibiotics were present in the cement, the technique of HPLCMS was preferred because it is highly sensitive and quantitative and allows individual measurement of the antibiotics within mixtures.24 The concentrations detected in this study are clinically relevant. The concentrations of gentamicin released from the plain 0.17 g discs (0.88% w/w) are in a similar range to those detected in vivo from beads and spacers mixed from the same cement.11 However, the mean concentration of gentamicin in the eluent fluid from beads in Anagnostakos et al’s11 work was in the region of 100 μg/mL. This is similar to the plain 0.17 g (0.88% w/w) discs in our study and much higher than the concentrations which they detected from spacers (approximately 20 ug/mL). However, even this concentration is less than the minimum inhibitory concentration (the lowest concentration of an antimicrobial that will inhibit the visible growth of an organism following overnight incubation)25 of approximately 128 μg/mL for Staphylococcus aureus or a typical coagulase negative Staphylococcus that are commonly implicated in prosthetic infections.26 Indenting the discs in this study took the concentration in the eluent fluid to approximately 200 μg/mL in the 0.17 g discs (0.88% w/w) and > 500 μg/mL with an indented 0.33 g disc (1.75% w/w). Furthermore, it has been shown that bacteria associated with a biofilm or orthopaedic infections are more resistant and higher doses of antibiotic are required for bactericidal activity of planktonic (freely suspended) cells.26
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In conclusion, indentation of a cement spacer increases the elution of gentamicin from a Hereaus spacer over a period of at least nine weeks. We suggest that this technique be considered whenever a spacer is used for the treatment of infection as the amount of antibiotic delivered is increased, thereby increasing the chances of successful eradication of infection. Author contributions: S. Saith: Designed and performed the experiments, wrote, edited and submitted manuscript. A. Paskins: Performed sample measurement and data analysis. T. Nichol: Performed sample measurement and data analysis, helped with editing of manuscript. T. Smith: Data analysis and manuscript editing. A Hamer: Conception of indentation, editing of manuscript. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by G. Scott and first proof edited by J. Scott.
References 1. Buchholz HW, Engelbrecht H. Depot effects of various antibiotics mixed with Palacos resins Chirurg 1970;41:511–515. (In German). 2. Elson RA, Jephcott AE, McGechie DB, Verettas D. Antibiotic-loaded acrylic cement. J Bone Joint Surg [Br] 1977;59-B:200–205. 3. No authors listed. National Joint Registry for England, Wales and Northern Ireland: 11th Annual Report, 2014. http://www.njrcentre.org.uk/njrcentre/Portals/0/Documents/England/Reports/11th_annual_report/ NJR%2011th%20Annual%20Report%202014.pdf (date last accessed 08 July 2015). 4. No authors listed. National Joint Registry for England and Wales: 6th Annual Report, 2009. http://www.njrcentre.org.uk/NjrCentre/Portals/0/ Sixth%20annual%20NJR%20report.pdf (date last accessed 08 July 2015). 5. Cooper HJ, Della Valle CJ. The two-stage standard in revision total hip replacement. Bone Joint J 2013;95-B:84–87. 6. Baker AS, Greenham LW. Release of gentamicin from acrylic bone cement. Elution and diffusion studies. J Bone Joint Surg [Am] 1988;70-A:1551–1557. 7. Seeley SK, Seeley JV, Telehowski P, et al. Volume and surface area study of tobramycin-polymethylmethacrylate beads. Clin Orthop Relat Res 2004;420:298–303. 8. Amin TJ, Lamping JW, Hendricks KJ, McIff TE. Increasing the elution of vancomycin from high-dose antibiotic-loaded bone cement: a novel preparation technique. J Bone Joint Surg [Am] 2012;94-A:1946–1951. 9. Masri BA, Duncan CP, Beauchamp CP, Paris NJ, Arntorp J. Effect of varying surface patterns on antibiotic elution from antibiotic-loaded bone cement. J Arthroplasty 1995;10:453–459.
10. Neut D, van de Belt H, van Horn JR, van der Mei HC, Busscher HJ. The effect of mixing on gentamicin release from polymethylmethacrylate bone cements. Acta Orthop Scand 2003;74:670–676. 11. Anagnostakos K, Wilmes P, Schmitt E, Kelm J. Elution of gentamicin and vancomycin from polymethylmethacrylate beads and hip spacers in vivo. Acta Orthop 2009;80:193–197. 12. Masri BA, Duncan CP, Beauchamp CP. Long-term elution of antibiotics from bone-cement: an in vivo study using the prosthesis of antibiotic-loaded acrylic cement (PROSTALAC) system. J Arthroplasty 1998;13:331–338. 13. Wroblewski BM. Leaching out from acrylic bone cement. Experimental evaluation. Clin Orthop Relat Res 1977;124:311–312. 14. Anagnostakos K, Kelm J. Enhancement of antibiotic elution from acrylic bone cement. J Biomed Mater Res B Appl Biomater 2009;90:467–475. 15. van de Belt H, Neut D, Uges DR, et al. Surface roughness, porosity and wettability of gentamicin-loaded bone cements and their antibiotic release. Biomaterials 2000;21:1981–1987. 16. Bayston R, Milner RD. The sustained release of antimicrobial drugs from bone cement. An appraisal of laboratory investigations and their significance. J Bone Joint Surg [Br] 1982;64-B:460–464. 17. Toms AD, Davidson D, Masri BA, Duncan CP. The management of peri-prosthetic infection in total joint arthroplasty. J Bone Joint Surg [Br] 2006;88-B:149–155. 18. Conway J, Mansour J, Kotze K, Specht S, Shabtai L. Antibiotic cement-coated rods: an effective treatment for infected long bones and prosthetic joint nonunions. Bone Joint J 2014;96-B:1349–1354. 19. Jaekel DJ, Day JS, Klein GR, et al. Do dynamic cement-on-cement knee spacers provide better function and activity during two-stage exchange? Clin Orthop Relat Res 2012;470:2599–2604. 20. Meyer J, Piller G, Spiegel CA, Hetzel S, Squire M. Vacuum-mixing significantly changes antibiotic elution characteristics of commercially available antibioticimpregnated bone cements. J Bone Joint Surg [Am] 2011;93-A:2049–2056. 21. Duey RE, Chong ACM, McQueen DA, et al. Mechanical properties and elution characteristics of polymethylmethacrylate bone cement impregnated with antibiotics for various surface area and volume constructs. Iowa Orthop J 2012;32:104–115. 22. Schurman DJ, Trindade C, Hirshman HP, et al. Antibiotic-acrylic bone cement composites. Studies of gentamicin and Palacos. J Bone Joint Surg [Am] 1978;60A:978–984. 23. Wahlig H, Dingeldein E. Antibiotics and bone cements. Experimental and clinical long-term observations. Acta Orthop Scand 1980;51:49–56. 24. Dodds S, Smith TJ, Akid R, et al. Contrasting effects of physical wear on elution of two antibiotics from orthopedic cement. Antimicrob Agents Chemother 2012;56:1471–1475. 25. Andrews JM. Determination of minimum inhibitory concentrations. J Antimicrob Chemother 2001;48(suppl1):5–16. 26. Coraça-Huber DC, Fille M, Hausdorfer J, Pfaller K, Nogler M. Staphylococcus aureus biofilm formation and antibiotic susceptibility tests on polystyrene and metal surfaces. J Appl Microbiol 2012;112:1235–1243.
THE BONE & JOINT JOURNAL
The cement spacer with multiple indentations INCREASING ANTIBIOTIC ELUTION USING A CEMENT SPACER ‘TEABAG’ S. Salih, A. Paskins, T. Nichol, T. Smith, A. Hamer From Northern General Hospital, Sheffield, United Kingdom
S. Salih, MA, MRCS, MD, Orthopaedic Registrar, A. Hamer, MD FRCS(Orth), Consultant Orthopaedic Surgeon, Department of Trauma and Orthopaedics Sheffield Teaching Hospitals NHS Foundation Trust, Herries Road, Sheffield S5 7AU, UK. A. Paskins, MRes, BSc (Hons), PhD Student, City Campus T. Nichol, BSc (Hons) MSc, PhD, Lecturer in Microbiology, City Campus T. Smith, MA, PhD, Professor of Microbiology, City Campus Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK. Correspondence should be sent to Mr S. Salih; e-mail: [email protected] ©2015 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620X.97B11. 35618 $2.00 Bone Joint J 2015;97-B:1519–24. Received 9 December 2014; Accepted after revision 2 July 2015
We investigated whether the indentation of bone cement spacers used in revision of infected joint arthroplasty with a MacDonald dissector increased the elution of antibiotic in vitro. A total of 24 cement discs containing either 0.17 g (0.88% w/w), 0.25 g (1.41% w/w), or 0.33 g (1.75% w/w) gentamicin of constant size were made. Of these, 12 were indented with the dissector. Each disc was immersed in ammonium acetate buffer in a sealed container, and fluid from each container was sampled at zero, one, three, six, 24, 48 and 72 hours and at one, and two weeks. The concentration of gentamicin in the fluid was analysed using high performance liquid chromatography mass spectrometry. The fluid sampled at 72 hours from the indented discs containing 0.17 g gentamicin (0.88% w/w) contained a mean of 113 mcg/ml (90.12 to 143.5) compared with 44.5 mcg/ml (44.02 to 44.90) in the fluid sampled from the plain discs (p = 0.012). In discs containing 0.33 g gentamicin (1.75% w/w), the concentration eluted from the indented discs at 72 hours was a mean of 316 mcg/ml (223 to 421) compared with a mean of 118 mcg/ml (100 to 140) from the plain discs (p < 0.001). At two weeks, these significant differences persisted. At nine weeks the indented discs eluted a greater concentration for all gentamicin doses, but the difference was only significant for the discs containing 0.17 g (0.88% w/w, p = 0.006). However if the area under the curve is taken as a measure of the total antibiotic eluted, the indented discs eluted more gentamicin than the plain discs for the 0.17 g (0.88% w/w, p = 0.031), the 0.25 g (1.41% w/w, p < 0.001) and the 0.33 g (1.75% w/w, p < 0.001) discs. When preparing antibiotic spacers for use in staged revision arthroplasty surgery we recommend indenting the spacer with a MacDonald dissector to increase the elution of antibiotic. Cite this article: Bone Joint J 2015;97-B:1519–24.
The addition of antibiotics to bone cement was introduced by Bucholz and Engelbrecht1 in the 1970s. Bone cement is used in a variety of orthopaedic applications including the treatment of infections where it acts as a carrier for the delivery of antibiotic to bone and softtissue.2 An increasing number of joint arthroplasties are being undertaken. More than 180 000 hip and knee arthroplasties were recorded in the National Joint Registry in England, Wales and Northern Ireland for 2014.3 During the last eight years the number of staged revisions recorded for infection has increased from 954 (24% of revisions)4 to 1317 (23%) for knees,3 and 804 (12%)4 to 1249 (13%)3 for hips. Although the rate of revision has not changed, the number of staged revisions for infection has increased proportionally to the increased number of primary arthroplasties.3,4 During the first stage, the infected components are removed and an antibiotic loaded cement
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spacer is often inserted after thorough debridement.5 Many bone cements are available with antibiotics incorporated in the powder. Further antibiotic may be added to cement powder before mixing with the monomer to tailor the spectrum of activity of the antibiotics in the cement. This requires the antibiotic to be available as a powder and to be thermostable.2 Gentamicin,2,6 tobramycin7 and vancomycin8 have been successfully mixed with cement and eluted at clinically significant levels. Cement spacers for revision arthroplasty are commercially available, but we prefer to make spacers intra-operatively for individual application. These spacers may be articulated or surround a temporary arthrodesis nail. In either case the senior author's (AJH) practice has been to mould the spacer after mixing. As the cement is curing several indentations are made in the surface of the cement using a Mac1519
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Table I. Number of indentations in each indented disc
Disc 1 Disc 2 Disc 3
0.88% w/w vacuum mixed indented
0.88% w/w hand mixed indented
1.41% w/w hand mixed indented
1.75% w/w hand mixed indented
34 32 32
28 34 27
26 25 31
29 31 30
Donald dissector. This process creates an indented surface on the spacer that looks like a teabag, which we hypothesised may increase the elution of antibiotic by increasing the surface area of the spacer. The elution of antibiotics from cement spacers appears to be affected by porosity,6 surface area9 and mixing technique.10 The elution increases if the surface area of the spacer increases. This was demonstrated by Masri et al9 using a patterned mould contributing to the improvement of a commercially available articulating spacer (PROSTALAC, DePuy Synthes, Leeds, United Kingdom). To our knowledge, the technique of indenting cement after mixing has not previously been described, and whether this technique increases the elution of antibiotic has not been investigated. The purpose of this study was to test, in vitro, whether indenting the spacer with a MacDonald dissector increases the elution of gentamicin from bone cement.
Materials and Methods A polythylene and stainless steel mould was manufactured in the workshop at the host institution allowing the creation of six cement discs with a diameter of 4 cm and a thickness of 1.2 cm from a standard double mix of cement (2 × 40 g of pack size polymer powder and 2 × 20 ml of monomer liquid) with no waste of cement. Discs containing 0.17 g of gentamicin (0.88% w/w) were made using a double mix of Heraeus Palacos R+G cement (each containing 0.5 g of gentamicin, Heraeus Medical GmbH, Wehreim, Germany) resulting in a total of 1 g of gentamicin distributed between six discs. Discs containing 0.25 g of gentamicin (1.41% w/w) were made with one mix of Heraeus Palacos R+G (0.5 g of gentamicin) and one mix of Heraeus Copal G+C (containing 1 g of gentamicin) resulting in a total of 1.5 g of gentamicin distributed between six discs. Discs containing 0.33 g of gentamicin (1.75% w/w) were made with two mixes of Heraeus Copal G+C (each containing 1 g of gentamicin) resulting in 2 g of gentamicin distributed among six discs. It should be noted that Copal G+C also contains clindamycin but its presence was not analysed in the subsequent work. Cement was stored at room temperature for 24 hours before mixing and all the discs were mixed sequentially on the same day. Cement was mixed for 30 seconds according to the manufacturer's instructions. Hand-mixed discs were mixed, without vacuum extraction attached, in a Summit multi-axial bowl (Summit Medical, Bourton-on-the-Water, United Kingdom) and the vacuum mixed discs were prepared in a Cemvac vacuum mixing syringe (Cemvac System
AB, Linkoping, Sweden). The cement was placed into the mould during the early application or working time (between two and three and a half minutes after the initiation of mixing) to produce six discs. During the late application and early curing time (after four minutes) the upper surface of three of the discs was indented with a MacDonald dissector, while the remaining three discs in the mould were left plain. Indentation was performed as would be in vivo. There was no predetermined density of indentations, but indentations were placed on the surface of the cement spacer in a manner which maximised the number of indentations without deforming the shape of the spacer. Once fully cured, the discs were removed from the mould and allowed to cool overnight at room temperature. Thus, there were three discs of each type, and a total of 24 discs. The number of indentations per disc is summarised in Table I. The depth of the indentations was measured using the MacDonald blade, which is 5 mm wide. The mean depth was 10 mm (9.5 to 10.5). Thus, the internal dimensions of each indentation were 1 cm2. Each disc was then immersed in 150 mL of 0.1 M ammonium acetate buffer (pH 7.4) in a sealed jar and stored at room temperature. Using a Gilson pipette (Gilson Inc, Middleton, Wisconsin), 500 μL of the solution was removed after stirring, to ensure uniform antibiotic dispersal, at zero, one, three, six, 24, 48, 72, 168 hours (one week), 336 hours (two weeks), and 1512 hours (nine weeks). Samples were frozen at -20oC until the time of analysis. Analysis of the concentration of gentamicin in each sample was undertaken using high performance liquid chromatography – mass spectometry (HPLC-MS) as follows. A 100 μl sample of fluid from each soaking disc was loaded into 2 ml autosampler vials (National Scientific, Rockwood, Tennessee) containing 200 μl inserts (Chromacol, Welwyn Garden City, United Kingdom) and loaded into the autosampler. HPLC-MS was performed using a Luna 5u C18 (2) 100 A (150 mm × 1.0 mm, particle size 5 μm) column (Phenomenex, Torrance, California). The system consisted of two Perkin Elmer series 200 micropumps (Perkin Elmer Incorporated, Shelton, Connecticut) coupled with a Finnigan MAT LCQ mass spectrometer (Thermo Electron Corporation, San Jose, California), operated using Xcalibre software (Thermo Electron Corporation). The system was run isocratically, with a mobile phase consisting of 20% MeOH (80% ddH2O) with 0.1% trifluoroacetic acid, with an acquisition time of eight minutes, plus five minutes equilibration time at the beginning of each run. The rate of flow THE BONE & JOINT JOURNAL
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Table II. Table showing mass in grams of each disc
Disc 1 Disc 2 Disc 3 Mean
0.88% w/w vacuum mixed plain
0.88% w/w vacuum mixed indented
0.88% w/w hand mixed plain
0.88% w/w hand mixed indented
1.41% w/w hand mixed plain
1.41% w/w hand mixed indented
1.75% w/w Hand mixed plain
1.75% w/w Hand mixed indented
17.70 17.80 19.40 18.30
19.00 19.00 18.50 18.83
18.40 18.60 18.90 18.63
18.40 20.10 18.10 18.87
19.20 18.50 19.20 18.97
18.60 18.90 19.09 18.86
19.50 19.10 18.70 19.10
19.20 18.90 20.00 19.37
through the column was 0.05 ml/min and scans were carried out in positive ion mode with selected ion monitoring detection at 478 m/z (± 1.00), corresponding with the protonated gentamicin parent ion. The mass spectrometer was tuned to the mass of 478 m/z using the autotune function. Statistical analysis. Results were recorded in Excel 2010 (Microsoft, Redmond, Washington), and statistical analysis performed using SPSS v.17 software (IBM Corp., Armonk, New York) with graphs produced in Prism 5 (Graphpad Software, San Diego, California). Data were shown to be normally distributed using both quantile-quantile normality plots and Shapiro-Wilk normality testing. The means for each type of disc were taken and compared using a one way analysis of variance (ANOVA) with Bonferroni's Multiple Comparisons post-test to compare means between plain discs and indented discs for each concentration with the significance level set at a p-value of < 0.05.
Results The mass of each disc is shown in Table II. There was no significant difference in mass between the discs of the different groups. The indented discs had a mean of 30 (standard deviation 3; 26 to 34) indentations per disc (Table I). Gentamicin became detectable in most of the fluid at one hour, and significant differences in the concentration of gentamicin eluted were seen between the plain discs and the indented discs by 48 hours (Fig. 1). For example, at one week, the mean concentration of gentamicin in the eluted fluid from the indented 0.33 g discs (1.75% w/w) was 481.1 μg/mL (449.2 to 546.8) compared with a mean of 193.0 μg/mL (176.3 to 202.6) in the plain discs (p < 0.001, one-way ANOVA with Bonferroni post-test). At nine weeks the increased elution from the indented discs compared with the plain discs persisted. Although the differences in concentration of gentamicin detected at this stage was significant only for the difference between the plain and indented hand-mixed discs containing 0.17 g of gentamicin (0.88% w/w, p = 0.006, Fig. 2), the total elution of gentamicin measured as the area under the curve (AUC) was significantly greater for all the hand-mixed discs (Fig. 3). The hand-mixed discs containing 0.17 g (0.88% w/w), 0.25 g (1.41% w/w), and 0.33 g (1.75% w/w) of gentamicin had a greater AUC (and hence a greater elution of antibiotic) when compared with their corresponding plain discs (p = 0.031 for 0.17 g discs and < 0.001 for 0.25 g and 0.33 g disc comparisons, one-way ANOVA with Bonferroni posttest). Although a greater amount of gentamicin was eluted VOL. 97-B, No. 11, NOVEMBER 2015
from the 0.17 g of gentamicin-containing vacuum mixed indented discs than from the corresponding discs made from hand-mixed cement, this difference did not reach statistical significance (p = 0.381). The total amount of eluted gentamicin can be estimated by extrapolating from the concentration sampled at nine weeks. The solution was stirred before sampling to ensure an even distribution of gentamicin throughout the buffer. Gentamicin is stable for several months in solution.6 With these assumptions, between 80% and 90% of the total gentamicin in the discs was eluted by nine weeks in the handmixed indented spacers, whereas between 40% and 60% was eluted in the plain discs.
Discussion These findings support the indentation of cement spacers with a MacDonald dissector to increase the elution of gentamicin from commercially available gentamicin loaded cement. Both the concentration of eluted antibiotic and the total released over a nine-week period is greater when the spacer is indented for a given mass and volume of cement. This work does not suggest a particular density of indentations, neither does it propose a configuration for the indentations. It is estimated that there is an increase in surface area of 1 cm2 with each 'stab' of the MacDonald dissector. Given that there was a mean of 30 indentations (26 to 34) per cement disc, it is estimated that the surface area of each disc was increased by 75% using this technique. It may be possible to further increase the surface area by using another configuration such as a ‘+’-shaped indentation. This was not tested because, in the authors’ experience, the generation of more complex patterns is more time consuming and is limited by the curing time of the cement. A MacDonald dissector was used because of its ready availability on a standard instrument tray and it can produce clean simple indentations. There are commercially available antibiotic loaded cement spacers that make use of a textured surface to increase the surface area and antibiotic elution.9 The use of cement beads has shown the same increase in antibiotic elution with increased surface area.11 However, preparing cement spacers by hand is less expensive and allows an antibiotic bespoke spacer to be made for each case. In addition, the increase in the surface area to volume ratio is potentially much greater when indenting with a MacDonald dissector when compared with a 10% increase gained by creating a surface pattern for manufacturing purposes.9
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2400
0.25g D 0.25g
2000 Conc (μg/mL)
2000 Conc (µg/mL)
2400
0.17g D 0.17g 0.17g VAC D 0.17g VAC
1600 1200 800
1600 1200 800
*
400
** ***
400
0
***
***
0 0
50
100 150 200 250 300 350 400 Time (hrs)
0
1512
50
100 150 200 250 300 Time (hrs)
1512
Fig. 1b
Fig. 1a
2400
0.33g D 0.33g
2000
Conc (μg/mL)
350 400
1600 1200 ***
800
***
***
***
400 0 0
50
100 150 200 250 300 350 400 Time (hrs)
1512
Fig. 1c Graphs showing the mean concentration of gentamicin eluted by cement discs containing a) 0.17 g gentamicin (0.88% w/w); b) 0.25 g gentamicin (1.41% w/w); and c) 0.33 g gentamicin (1.75% w/w). Error bars represent standard deviations (n = 3).* p = 0.039; ** p = 0.003; *** p < 0.001; VAC, vacuum mixed disc; D, perforated disc.
The differences in the elution of gentamicin between the plain and indented discs were not statistically significant until 48 hours. This may be because the differences in concentration are small, and there is inherent variability in the HPLC-MS readings. However, by 48 hours there was a highly significant difference between the indented and plain 1.41% w/w (p < 0.001) and 1.75% w/w discs (p < 0.001). The spacers continued to elute antibiotic for at least nine weeks, similar to previous findings.9,12 Masri et al9 suggested that the difference between the textured and plain spacers was significant up to two weeks only. This may be accounted for by the rate of elution. It may be that the rate of elution is greater with a greater surface area. There is a finite amount of antibiotic that can be released from a spacer, and this may be the same for any given volume of antibiotic loaded cement. Given that the difference in surface area was only 10%, in the investigation by Masri et al9 the time taken for the plain disc to 'catch up' may have been only two weeks. In this study, indenting the spacer
increased the surface area of spacer by 75% and therefore, a longer period may be required before the plain discs would be shown to release a similar amount of antibiotic. However, given that a high peak dose is desired as quickly as possible for the best chance of eradicating microorganisms, indentation of the spacer is still desirable. At two weeks the elution of gentamicin from the handmixed indented discs was at least double that of the corresponding plain discs, suggesting that the increased elution of gentamicin was not purely a surface area phenomenon. The mechanism of antibiotic elution is debated. Early experiments with sodium chloride supported the theory that the release of antibiotic was a passive surface phenomenon, and that a greater surface area would increase elution.13 Others have suggested that diffusion of antibiotic may occur through the matrix of bone cement14 but it is more likely that this occurs because of a series of microscopic cracks and pores in the cement effectively increasing its surface area.6,15,16 Indenting the spacer with a dissector THE BONE & JOINT JOURNAL
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2500
Conc (∝g/mL)
2000 *
1500 1000
0.33g D
0.33g
0.25g D
0.25g
0.17g D
0.17g
0.17g VAC
0
0.17g VAC D
500
Fig. 2 Graph showing the mean concentration of gentamicin in eluent at nine weeks. Error bars represent standard deviations.* p < 0.006; VAC, Vacuum mixed disc; D, perforated disc; 0.17 g, 0.88% w/w disc; 0.25 g, 1.41% w/w disc; 0.33 g, 1.75% w/w disc.
2 × 106
AUC (µghrs)
† 1.5 × 106
† *
1 × 106
5 × 105
0.33g D
0.33 g
0.25g D
0.25 g
0.17g D
0.17 g
0.17g VAC D
0.17g VAC
0
Fig. 3 Graph showing the mean area under curve at nine weeks. Error bars represent standard deviations.* p = 0.031; † p < 0.001; VAC, Vacuum mixed disc; D, perforated disc; 0.17 g, 0.88% w/w disc; 0.25 g, 1.41% w/ w disc; 0.33 g, 1.75% w/w disc.
may increase the effective surface area by more than 75% if the indentations expose cracks and pits within the body of the spacer, which would otherwise have not been in contact with the surface. Although this may weaken the cement, the purpose of a cement spacer in surgery for prosthetic joint infection is to deliver antibiotic at a higher concentration to the local tissues than could be achieved by parenteral administration5,12 and to maintain soft-tissue tension and limb length,17,18 rather than to offer structural or loadbearing support. In most cases, spacers are temporary,5 and increased porosity has been shown not to affect a spacer's function adversely or to cause failure when used in a staged revision procedure.19 VOL. 97-B, No. 11, NOVEMBER 2015
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A limitation of this work is that only one antibiotic was assayed, however the purpose of this study was to determine whether indentation of a spacer with a MacDonald dissector would increase the elution of antibiotic compared with a plain spacer. Gentamicin is commonly added to commercially-prepared antibiotic-loaded bone cement.5,18 Furthermore, the elution of gentamicin from Palacos has been shown to be more consistent and greater than its elution from other brands.14,16,20 The elution of gentamicin in this study did not seem to be affected by the presence of clindamycin in the discs containing Copal cement, unlike other work in which the presence of several antibiotics in cement appeared to inhibit elution.21 Although there were only three discs per condition, the results were both statistically and clinically significant. The range of concentration in the indented discs reflects the variability in clinical practice. Access to the spacer in vivo may be limited by the local anatomy or the curing time and different spacers will have a different number of indentations. Ammonium acetate buffer rather than serum was used to allow the use of HPLC-MS to give quantitative results. Other studies have shown that the elution of antibiotic from cement into buffer is the same22 or less23 than that into serum. Much of the early work on antibiotic elution from cement used agar plate diffusion assays, where the cement disc or inhibition of bacterial growth by the eluent fluid on an agar plate is used to estimate the concentration of antibiotic which is released.2,6,21-23 Here, since two antibiotics were present in the cement, the technique of HPLCMS was preferred because it is highly sensitive and quantitative and allows individual measurement of the antibiotics within mixtures.24 The concentrations detected in this study are clinically relevant. The concentrations of gentamicin released from the plain 0.17 g discs (0.88% w/w) are in a similar range to those detected in vivo from beads and spacers mixed from the same cement.11 However, the mean concentration of gentamicin in the eluent fluid from beads in Anagnostakos et al’s11 work was in the region of 100 μg/mL. This is similar to the plain 0.17 g (0.88% w/w) discs in our study and much higher than the concentrations which they detected from spacers (approximately 20 ug/mL). However, even this concentration is less than the minimum inhibitory concentration (the lowest concentration of an antimicrobial that will inhibit the visible growth of an organism following overnight incubation)25 of approximately 128 μg/mL for Staphylococcus aureus or a typical coagulase negative Staphylococcus that are commonly implicated in prosthetic infections.26 Indenting the discs in this study took the concentration in the eluent fluid to approximately 200 μg/mL in the 0.17 g discs (0.88% w/w) and > 500 μg/mL with an indented 0.33 g disc (1.75% w/w). Furthermore, it has been shown that bacteria associated with a biofilm or orthopaedic infections are more resistant and higher doses of antibiotic are required for bactericidal activity of planktonic (freely suspended) cells.26
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In conclusion, indentation of a cement spacer increases the elution of gentamicin from a Hereaus spacer over a period of at least nine weeks. We suggest that this technique be considered whenever a spacer is used for the treatment of infection as the amount of antibiotic delivered is increased, thereby increasing the chances of successful eradication of infection. Author contributions: S. Saith: Designed and performed the experiments, wrote, edited and submitted manuscript. A. Paskins: Performed sample measurement and data analysis. T. Nichol: Performed sample measurement and data analysis, helped with editing of manuscript. T. Smith: Data analysis and manuscript editing. A Hamer: Conception of indentation, editing of manuscript. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by G. Scott and first proof edited by J. Scott.
References 1. Buchholz HW, Engelbrecht H. Depot effects of various antibiotics mixed with Palacos resins Chirurg 1970;41:511–515. (In German). 2. Elson RA, Jephcott AE, McGechie DB, Verettas D. Antibiotic-loaded acrylic cement. J Bone Joint Surg [Br] 1977;59-B:200–205. 3. No authors listed. National Joint Registry for England, Wales and Northern Ireland: 11th Annual Report, 2014. http://www.njrcentre.org.uk/njrcentre/Portals/0/Documents/England/Reports/11th_annual_report/ NJR%2011th%20Annual%20Report%202014.pdf (date last accessed 08 July 2015). 4. No authors listed. National Joint Registry for England and Wales: 6th Annual Report, 2009. http://www.njrcentre.org.uk/NjrCentre/Portals/0/ Sixth%20annual%20NJR%20report.pdf (date last accessed 08 July 2015). 5. Cooper HJ, Della Valle CJ. The two-stage standard in revision total hip replacement. Bone Joint J 2013;95-B:84–87. 6. Baker AS, Greenham LW. Release of gentamicin from acrylic bone cement. Elution and diffusion studies. J Bone Joint Surg [Am] 1988;70-A:1551–1557. 7. Seeley SK, Seeley JV, Telehowski P, et al. Volume and surface area study of tobramycin-polymethylmethacrylate beads. Clin Orthop Relat Res 2004;420:298–303. 8. Amin TJ, Lamping JW, Hendricks KJ, McIff TE. Increasing the elution of vancomycin from high-dose antibiotic-loaded bone cement: a novel preparation technique. J Bone Joint Surg [Am] 2012;94-A:1946–1951. 9. Masri BA, Duncan CP, Beauchamp CP, Paris NJ, Arntorp J. Effect of varying surface patterns on antibiotic elution from antibiotic-loaded bone cement. J Arthroplasty 1995;10:453–459.
10. Neut D, van de Belt H, van Horn JR, van der Mei HC, Busscher HJ. The effect of mixing on gentamicin release from polymethylmethacrylate bone cements. Acta Orthop Scand 2003;74:670–676. 11. Anagnostakos K, Wilmes P, Schmitt E, Kelm J. Elution of gentamicin and vancomycin from polymethylmethacrylate beads and hip spacers in vivo. Acta Orthop 2009;80:193–197. 12. Masri BA, Duncan CP, Beauchamp CP. Long-term elution of antibiotics from bone-cement: an in vivo study using the prosthesis of antibiotic-loaded acrylic cement (PROSTALAC) system. J Arthroplasty 1998;13:331–338. 13. Wroblewski BM. Leaching out from acrylic bone cement. Experimental evaluation. Clin Orthop Relat Res 1977;124:311–312. 14. Anagnostakos K, Kelm J. Enhancement of antibiotic elution from acrylic bone cement. J Biomed Mater Res B Appl Biomater 2009;90:467–475. 15. van de Belt H, Neut D, Uges DR, et al. Surface roughness, porosity and wettability of gentamicin-loaded bone cements and their antibiotic release. Biomaterials 2000;21:1981–1987. 16. Bayston R, Milner RD. The sustained release of antimicrobial drugs from bone cement. An appraisal of laboratory investigations and their significance. J Bone Joint Surg [Br] 1982;64-B:460–464. 17. Toms AD, Davidson D, Masri BA, Duncan CP. The management of peri-prosthetic infection in total joint arthroplasty. J Bone Joint Surg [Br] 2006;88-B:149–155. 18. Conway J, Mansour J, Kotze K, Specht S, Shabtai L. Antibiotic cement-coated rods: an effective treatment for infected long bones and prosthetic joint nonunions. Bone Joint J 2014;96-B:1349–1354. 19. Jaekel DJ, Day JS, Klein GR, et al. Do dynamic cement-on-cement knee spacers provide better function and activity during two-stage exchange? Clin Orthop Relat Res 2012;470:2599–2604. 20. Meyer J, Piller G, Spiegel CA, Hetzel S, Squire M. Vacuum-mixing significantly changes antibiotic elution characteristics of commercially available antibioticimpregnated bone cements. J Bone Joint Surg [Am] 2011;93-A:2049–2056. 21. Duey RE, Chong ACM, McQueen DA, et al. Mechanical properties and elution characteristics of polymethylmethacrylate bone cement impregnated with antibiotics for various surface area and volume constructs. Iowa Orthop J 2012;32:104–115. 22. Schurman DJ, Trindade C, Hirshman HP, et al. Antibiotic-acrylic bone cement composites. Studies of gentamicin and Palacos. J Bone Joint Surg [Am] 1978;60A:978–984. 23. Wahlig H, Dingeldein E. Antibiotics and bone cements. Experimental and clinical long-term observations. Acta Orthop Scand 1980;51:49–56. 24. Dodds S, Smith TJ, Akid R, et al. Contrasting effects of physical wear on elution of two antibiotics from orthopedic cement. Antimicrob Agents Chemother 2012;56:1471–1475. 25. Andrews JM. Determination of minimum inhibitory concentrations. J Antimicrob Chemother 2001;48(suppl1):5–16. 26. Coraça-Huber DC, Fille M, Hausdorfer J, Pfaller K, Nogler M. Staphylococcus aureus biofilm formation and antibiotic susceptibility tests on polystyrene and metal surfaces. J Appl Microbiol 2012;112:1235–1243.
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