What evidence supports the use of antibiotic-loaded bone cement to prevent infection in primary hip and knee arthroplasty?

Introduction

Periprosthetic joint infection is a concern in total hip arthroplasty (THA) and total knee arthroplasty (TKA).¹ Although the incidence of infection is approximately 1% to 2.5% in both procedures, it is the leading and third-leading cause of revision surgeries in THA and TKA, respectively, and is difficult to manage and heal.^1-4 Bone cement, a viscous paste compounded from powder polymethylmethacrylate and a liquid methylmethacrylate, is used in orthopedic procedures to help fix prostheses to bone.¹ Antibiotics can be added to the bone cement during its compounding to achieve high and prolonged local drug concentrations to prevent infection.² Debate has existed over the use of antibiotic-loaded bone cement (ALBC) because of the risks for antibiotic resistance and reduction in structural integrity of the cement, as well as the efficacy of this practice. This review summarizes literature describing the efficacy of ALBC when used to prevent infection in primary THA and TKA.

Literature review

Numerous studies have been conducted that evaluated the use of ALBC in both TKA and THA, which have been included in meta-analyses. A recent meta-analysis of high-quality studies of prophylactic ALBC in primary TKA evaluated the incidence of surgical site infection (SSI) that was either deep or superficial.⁵ Pooled data from 6637 patients in 5 studies found the risk of deep SSI was not significantly different with ALBC in analyses of prospective and retrospective studies (relative risk [RR], 0.75; 95% confidence interval [CI], 0.43 to 1.33), nor when analysis was restricted to only 3 randomized controlled trials (RCTs; RR, 0.28; 95% CI, 0.04 to 1.25). Prophylactic ALBC also provided no significant reduction in the incidence of superficial SSIs (RR, 0.28; 95% CI, 0.04 to 1.25). No adverse events were reported in any of the included studies. Additionally, data from registries of TKA-associated infection have reported conflicting findings for the use of ALBC in TKA.³ A Finnish registry found a higher risk of infection in patients who did not receive ALBC in primary TKA (RR, 1.35; 95% CI, 1.01 to 1.81), but data from an Australian registry found no difference in 1-, 5-, or 13-year infection or revision rates. Similarly, revision rates with ALBC were no different from non-ALBC among 36,000 patients in a Canadian registry of TKA.

In THA, results are less conflicting and overall demonstrate efficacy of prophylactic use of ALBC. The risk of infection in primary THA with ALBC was significantly reduced compared to control in a meta-analysis of 7 studies of approximately 7,000 patients (RR, 0.506; 95% CI, 0.341 to 0.751).⁶ This meta-analysis also found the risk of revision was significantly reduced with ALBC (RR, 0.721; 95% CI, 0.628 to 0.828).

Another meta-analysis of 8 RCTs combined results from settings of both THA and TKA, and again found no overall significant benefit with ALBC.⁷ Compared to control treatment with either plain bone cement or systemic antibiotics, ALBC did not significantly decrease the incidence of superficial infection, although it was associated with significant reductions in deep infection (RR, 0.41; 95% CI, 0.17 to 0.97). However, in subgroup comparisons to plain bone cement, neither outcome was significantly improved with ALBC; only comparisons to systemic antibiotics showed reduced deep infection with ALBC (RR, 0.37; 95% CI, 0.14 to 0.98). Conversely, compared to systemic antibiotics, ALBC significantly increased the risk of superficial infection (RR, 1.48; 95% CI, 1.1 to 2.0). In subgroup analyses of THA and TKA individually, results again showed significantly reduced deep infection rates with ALBC in THA (RR, 0.21; 95% CI, 0.08 to 0.50), but no effect in TKA. Another more recent meta-analysis reported consistent findings of no overall reduction in infection with ALBC when combining data from trials of THA, TKA, and total shoulder arthroplasties.⁸

While these meta-analyses indicate the benefit of ALBC may be limited to THA, several shortcomings leave questions on the true efficacy of ALBC. First, the methodologic quality of included studies was low, as the evidence rating systems scored few trials above 2 points on the maximum 5-point Jadad scale of trial quality.⁷ Secondly, the heterogeneity of interventions may lead to confounding. For example, because commercially available ALBC products were not available for all antibiotics, the type and amount of antibiotic included in ALBC was based on clinicians’ discretion and may vary within and between studies; this was not controlled for in meta-analyses. Likewise, the type of prosthesis was not controlled for, even though the nature of its material could differentially influence the production of biofilm.² Comparisons of the type of antibiotic used were not consistently performed, and leave questions regarding the most efficacious product. Lastly, studies included in these meta-analyses have spanned continents and decades, leaving the potential for regional and temporal differences in microbiology and orthopedic procedures to influence outcomes.

Application to practice

Until further data or guidance becomes available, clinicians who choose to use ALBC should consider several important points to ensure optimal outcomes. First, when compounding ALBC, the selected antibiotic must possess a spectrum of activity against likely gram-positive and gram-negative pathogens.⁹ Aminoglycosides and vancomycin are commonly used, although use of penicillins, cephalosporins, macrolides, fluoroquinolones, and linezolid has been reported. The antibiotic also should be available in powder form because addition of liquid antibiotics significantly decreases the mechanical strength of the bone cement.^2,9 Additionally, because the polymerization of the cement is an exothermic reaction reaching temperatures up to 80° C, the antibiotic should be chemically and thermally stable at these temperatures. The dose of the antibiotic must also be considered. Generally, recommendations are that the amount of antibiotic should range from 10% to 15% of the total weight of the cement (eg, 4 to 6 g per 40 g of cement).⁹ Some argue that in settings of infection treatment, antibiotic doses above 2 g per each 40 g of cement should be used. In contrast, in prophylactic settings where the primary function of the cement is for fixation, doses lower than 2 g per 40 g of cement have been recommended.²

Commercially available ALBC is also an option that could obviate the need for compounding. Commercial ALBC products are available with premixed tobramycin (eg, Simplex P with Tobramycin); gentamicin (eg, Cemex Genta; Cobalt G-HV; DePuy CMW 1, 2, and 3; Palacos LV+G; Palacos R+G; Refobacin LV; Refobacin Plus; Refobacin R; Smartset GHV; Smartset GMV); and gentamicin and clindamycin (eg, Refobacin Revision). Clinicians should be aware that these products are regulated by the Food and Drug Administration as devices via 510(k) or Premarket Authorization (PMA) pathways, and therefore may require less clinical study to achieve marketing approval compared to traditional drug approval. Such devices only need to demonstrate substantial equivalence to legally marketed predicate devices (for the brief 510k pathway approval, which does not usually require human data) or safety and efficacy (for the more rigorous PMA pathway approval, which requires data from human clinical studies).¹⁰¹² Therefore, a review of published clinical literature for a particular product may be helpful in determining the most appropriate, safe, and effective commercial ALBC product for a particular use.

Conclusion

While meta-analyses support the ability of ALBC to reduce infection in THA, currently available data do not suggest benefit in TKA. Limitations in the design of studies included in meta-analyses leave questions on the true benefit of ALBC, as they were commonly uncontrolled or retrospective in design. Until definitive guidance is available on its use in primary THA and TKA, clinicians who choose to use ALBC in arthroplasty procedures should select an appropriate quantity of the mixed antibiotic if the ALBC is to be compounded or consider the use of commercially available ALBC products.

August 2016

The information presented is current as of July 7, 2016.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

References

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2.         Bistolfi A, Massazza G, Verne E, et al. Antibiotic-loaded cement in orthopedic surgery: a review. ISRN Orthop. 2011;2011:290851.

3.         Hinarejos P, Guirro P, Puig-Verdie L, et al. Use of antibiotic-loaded cement in total knee arthroplasty. World J Orthop. 2015;6(11):877-885.

4.         Lindeque B, Hartman Z, Noshchenko A, Cruse M. Infection after primary total hip arthroplasty. Orthopedics. 2014;37(4):257-265.

5.         Zhou Y, Li L, Zhou Q, et al. Lack of efficacy of prophylactic application of antibiotic-loaded bone cement for prevention of infection in primary total knee arthroplasty: results of a meta-analysis. Surg Infect (Larchmt). 2015;16(2):183-187.

6.         Parvizi J, Saleh KJ, Ragland PS, Pour AE, Mont MA. Efficacy of antibiotic-impregnated cement in total hip replacement. Acta Orthop. 2008;79:335-341.

7.         Wang J, Zhu C, Cheng T, et al. A systematic review and meta-analysis of antibiotic-impregnated bone cement use in primary total hip or knee arthroplasty. PLoS One. 2013;8(12):e82745.

8.         Yi Z, Bin S, Jing Y, Zongke Z, Pengde K, Fuxing P. No decreased infection rate when using antibiotic-impregnated cement in primary total joint arthroplasty. Orthopedics. 2014;37(12):839-845.

9.         Soares D, Leite P, Barreira P, Aido R, Sousa R. Antibiotic-loaded bone cement in total joint arthroplasty. Acta Orthop Belg. 2015;81(2):184-190.

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11.       Premarket approval (PMA). US Food and Drug Administration website. http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/premarketapprovalpma/default.htm. Updated July 8, 2016. Accessed July 11, 2016.

12.       Overview of device regulation. US Food and Drug Administration website. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/. Updated August 14, 2015. Accessed July 25, 2016.