Most authors do not recommend using antibiotic cement for primary arthroplasty, first of all because the antibiotic changes the mechanic features of the cement (even though most studies show that if the antibiotic represents less than 5% of the total weight of the cement, it does not modify its structure and its resistance), and second of all because its use on a large scale might result in the development of antibiotic resistant strains.^1-3

Antibiotic-based cement can be used in primary arthroplasty surgeries when the patient has a high surgical risk, in seniors, in patients with immunodepression, polyarthritis, diabetes, malnutrition or with a history of periprosthetic infection.^4,5

The main use of antibiotic loaded cement is in septic revisions. These revisions can be made either in one stage or in two stages. In the case of one-stage septic revision, first the prosthesis is removed along with all the surrounding tissue, then an abundant lavage is performed with antiseptic solutions (8-10 L) and after that the new prosthesis is inserted along with the antibiotic loaded cement.^4-6 In two-stage revisions, after the prosthesis is removed, the surrounding tissue excised and the abundant lavage performed, an antibiotic-loaded spacer is inserted (in correlation with the results from the antibiogram).^4,5 The spacer can be fixed or articulating. For a better preservation of the knee range of motion the articulating one is preferred.⁶

The role of this spacer is to release antibiotic in situ, to prevent the formation of biofilm at this level, to prevent the retraction of the soft tissues, preserving the articular space and facilitating the insertion of the new prothesis after 6-8 weeks.^7-10

Besides the local antibiotic, i.v. antibiotics will be administered for a minimum of 3 weeks, followed by oral antibiotherapy up to 6-8 weeks.^11,12If 6 weeks after prosthesis extraction the laboratory evaluations are normal, the articular puncture is negative and the health status of the patient allows it, we proceed to the second surgery to remove the spacer and insert the new prosthesis. If the infection is still present, inserting the prosthesis will be postponed and the whole process will be repeated (debridement, spacer change, i.v. antibioterapy followed by oral antibiotherapy). Exceeding 6-8 weeks of antibiotic treatment does not appear to benefit the patient and the spacer will no longer release the antibiotic in situ, and replacing it with a new one will be necessary.^11,12 Most studies recommend keeping the antibiotic spacers for up to 45 days in two-stage revisions.⁸

We performed a prospective study in order to evaluate in vitro for how long gentamicin- and vancomycin-loaded cements still manage to reach the minimum inhibitory concentration, specifically to assess if, after 45 days, the cement still fulfills its antibiotic purpose apart from the mechanical one, as a spacer.^8,9,10 We used two types of antibiotic-loaded acrylic cement (polymethylmethacrylate – PMMA). One was prefabricated, containing 40 g of cement powder and 2 g of gentamicin. The second one was handmade containing 40 g of cement powder and 2 g of vancomycin.

In a sterile environment, to avoid possible contamination, we added the solvent to the powder, we mixed for 30 seconds, we waited for 3 minutes after which we manually created 90 tablets, approximately 3x3 mm each, from each type of cement. The tablets were allowed roughly 17 min to harden and then stowed, each one in a sterile container with 2 mL phosphate-buffered saline (PBS).

Every day, we took two cement tablets, one with vancomycin and one with gentamicin and transferred them to an agar culture environment (Mueller Hinton E agar – MHE) previously inoculated with 0.05 McFarlandunits of Staphylococcus aureus reference strain ATCC 25923. The dish was incubated at 37°C for 24 hours, after which the sample was read measuring the inhibition area around the cement tablet.

We changed the saline daily from the unused samples by moving them in different containers trying therefore to reproduce the in vitro environment, the constant renewal around the cement (spacer).

We read the results daily, by measuring the inhibition area around the cement.

For both types of cement the maximum inhibition area was recorded in the first day and it measured 16/17 mm in the vancomycin cement and 34/40 mm in the one with gentamicin.

Both antibiotics had a good minimal inhibition concentration (MIC) in the first 6 weeks of the study (Figure 1).

Figure1. Inhibition area for gentamicin (up) and for vancomycin (down)

We obtained inhibition areas exceeding 10 mm around the cement in the first 45 days.

In the 60^th day, the inhibition area around the gentamicin cement started to decrease progressively under 10 mm and on the 64^thday it disappeared completely.

Regarding the vancomycin cement, the inhibition area started to decrease from the 66^th day, until becoming completely absent on the 68^thday (Figure 2).

Figure 2. The lack of inhibition area for both antibiotics

After the disappearance of the inhibition areas, we carried on plating samples for 2 more weeks in order to observe the occurrence of possible changes (Table 1). All samples had no inhibition area, the final read taking place 82 days after we had produced the cement.

 

Antibiotic-loaded spacers are used in periprosthetic infections for their local antimicrobial effect, but it is unclear for how long the antibiotics that the spacers release still have a bactericidal level in the joint. Therefore, we performed a study to assess whether an antibiotic can have effect in the area around the spacer 6or more weeks after implantation and whether the concentration remains higher than the MIC.

We recognize some limitations to our study. We had just two types of antibiotics (the most frequently used). The fluid exchange around the bone cement in vitro is different than in vivo, so the vascular supply may cause different wash-out of antibiotics from the cement.

The local use of an antimicrobial agent could determine the occurrence of antibiotic resistance, when the antibiotic levels decrease below the MIC.

The data we obtained with gentamicin and vancomycin may not be relevant for other antibiotics. Our study showed that the antibiotics we used were released locally by the spacer for 6 weeks. We continued to analyze the samples until we lost the bactericidal effect and for 14 more days afterwards.

For both types of antibiotic cement, we obtained a bactericidal effect (an area of inhibition) in first 8 weeks of the study. Maintaining a spacer in place for more than 8 weeks could bring no benefit. On the contrary it might allow bacteria to adhere and form a biofilm, making the antibiotherapy useless after 8 weeks, if the pathogenic agent is still present.

The spacer releases sufficient amounts of antibiotics, helping the treatment of infections and is not just filling the empty space. Together with i.v. antibiotherapy, extended tissue removal and thorough lavage, the spacer may play an essential role in obtaining a clean bone structure on which a new prosthetic can be inserted.

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https://doi.org/10.1097/01.blo.0000143739.07632.7c

2. Hofmann AA, Goldberg TD, Tanner AM, Cook TM. Ten-year experience using an articulating antibiotic cement hip spacer for the treatment of chronically infected total hip. J Arthroplasty. 2005;20:874-9.

https://doi.org/10.1016/j.arth.2004.12.055

3. Lieberman JR, Callaway GH, Salvati EA, Pellicci PM, Brause BD. Treatment of the infected total hip arthroplasty with a two-stage reimplantation protocol. Clin Orthop Relat Res. 1994;(301):205-12.

https://doi.org/10.1097/00003086-199404000-00032

4. Lichstein P, Su S, Hedlund H, et al. Treatment of periprosthetic knee infection with a two-stage protocol using static spacers. Clin Orthop Relat Res. 2016;474:120-5.

https://doi.org/10.1007/s11999-015-4443-2

5. Mortazavi SM, Vegari D, Ho A, Zmistowski B, Parvizi J. Two-stage exchange arthroplasty for infected total knee arthroplasty: predictors of failure. Clin Orthop Relat Res. 2011;469:3049-54.

https://doi.org/10.1007/s11999-011-2030-8

6. Haddad FS, Sukeik M, Alazzawi S. Is single-stage revision according to a strict protocol effective in treatment of chronic knee arthroplasty infections? Clin Orthop Relat Res. 2015;473:8-14.

https://doi.org/10.1007/s11999-014-3721-8

7. Fink B, Grossmann A, Fuerst M, Schäfer P, Frommelt L. Two-stage cementless revision of infected hip endoprostheses. Clin Orthop Relat Res. 2009;467:1848-58.

https://doi.org/10.1007/s11999-008-0611-y

8. Fink B, Vogt S, Reinsch M, Büchner H. Sufficient release of antibiotic by a spacer 6 weeks after implantation in two-stage revision of infected hip prostheses. Clin Orthop Relat Res. 2011;469:3141-7.

https://doi.org/10.1007/s11999-011-1937-4

9. Anagnostakos K, Fürst O, Kelm J. Antibiotic-impregnated PMMA hip spacers: Current status. Acta Orthop. 2006;77:628-37.

https://doi.org/10.1080/17453670610012719

10. Hanssen AD, Spangehl MJ. Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements. Clin Orthop Relat Res. 2004;(427):79-85.

https://doi.org/10.1097/01.blo.0000143806.72379.7d

11. Bertazzoni Minelli E, Benini A, Magnan B, Bartolozzi P. Release of gentamicin and vancomycin from temporary human hip spacers in two-stage revision of infected arthroplasty. J Antimicrob Chemother. 2004;53:329-34.

https://doi.org/10.1093/jac/dkh032

12. Li C, Renz N, Trampuz A. Management of periprosthetic joint infection. Hip Pelvis. 2018;30:138-146.

https://doi.org/10.5371/hp.2018.30.3.138

13. Chaussade H, Uçkay I, Vuagnat A, et al. Antibiotic therapy duration for prosthetic joint infections treated by Debridement and Implant Retention (DAIR): Similar long-term remission for 6 weeks as compared to 12 weeks. Int J Infect Dis. 2017;63:37-42.

https://doi.org/10.1016/j.ijid.2017.08.002