Antibiotic Loaded Bone Cement in Primary Total Hip and Knee Arthroplasty

Abstract

Background

Antibiotic loaded bone cement (ALBC) is currently approved by the United States Food and Drug Administration for use in revision arthroplasty for periprosthetic joint infection, but not primary arthroplasty. Still, ALBC is commonly used prophylactically in primary arthroplasty.

Methods

Committee statements, registry data, and clinical and basic science research on ALBC in primary hip and knee arthroplasty were reviewed.

Conclusion

High-level evidence is limited at the current time. Clinical trials enrolling patients at highest risk for PJI are warranted to provide guidance for appropriate use of ALBC in the primary setting.

Introduction

Antibiotic loaded bone cement (ALBC) is one form of local antibiotic delivery that allows for high local concentration of antibiotics, classically with reduced risk for systemic toxicity.^1,2 ALBC was first described by Buchholz in 1970 at the renowned Endo-Klinik in Hamburg, Germany. ³ The mixture of polymethylmethacralate (PMMA) cement with antibiotics can deliver local concentrations of antibiotics much higher than that seen with systemic treatment. ² It is generally used in two different modes: in the form of a fixation interface, or as an antibiotic spacer. As a fixation interface, ALBC may be used prophylactically in primary total joint arthroplasty (TJA), which is currently controversial as evidence for prevention of periprosthetic joint infection (PJI) is mixed. We intended to review the literature on prophylactic ALBC use, potential indications, and modes of use.

Committee Statements

Several consensus groups have issued statements regarding ALBC in primary joint arthroplasty. The American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guideline from 2019 noted limited evidence to support routine ALBC in total knee arthroplasty (TKA), but their limited recommendations change for total hip arthroplasty (THA). ⁴ The International Consensus Meeting on Musculoskeletal Infection (ICMMI) did not support routine use in primary TJA, but did support a role for use in high-risk patients. ⁵ The 2019 ALBC Research Workgroup note a lack of level 1 studies to support prophylactic use. ⁶ While 38% of surgeons in the workgroup reported use of ALBC in all cemented primary arthroplasties, 67% restricted use to patients at risk for infection. ⁶ Furthermore, in North America, the Food and Drug Administration (FDA) has approved ALBC only for revision arthroplasty in treating PJI.

Registry Data

Routine prophylactic ALBC has been common internationally, and observational registry data is mixed. While it is important to consider the inherent limitations of registry data: lack of standardization in surgical practices and limitations in data collected, several registries seem to support ALBC in primary arthroplasty. Two reports on the Norwegian arthroplasty register on cemented, primary total hip arthroplasty conclude that revision for infection is lowest when prophylactic ALBC is used in combination with systemic antibiotics.^7,8 Regarding primary TKA, results from the Finnish Arthroplasty register, ⁹ United Kingdom, ¹⁰ and Australia ¹¹ support a lower risk of revision for infection in TKA.

In contrast, a report from the Canadian registry demonstrates no significant benefit in primary TKA, ¹² while reports from American ¹³ and New Zealand ¹⁴ registries indicate a paradoxical increase in risk for infection. The authors who reported on the American and New Zealand registries do note that selection bias may have skewed results, as ALBC use was not routine, and surgeons may have employed ALBC in high-risk populations.^13,14

Pooled Data

Two recent systematic reviews have been published on the subject. Farhan-Alaine et al performed a systematic review and found an association with decreased PJI in primary THA, but not TKA. The review included registry data, as well as a single, large RCT that failed to find a treatment effect in all-comers. Sebastian et al reviewed Level 1 studies and concluded that prophylactic ALBC had a protective effect against PJI. Importantly, the studies included in this review had heterogenous inclusion criteria; one of the trials was limited to high-risk patients.

Potential Drawbacks

As discussed, prophylactic ALBC for primary arthroplasty may either be used in all-comers, or on a more limited basis in high-risk patients. Two randomized controlled trials have failed to demonstrate an advantage over perioperative systemic antibiotics in all-comers.^15,16 Selective use of ALBC may be more responsible, as concerns beyond ineffectiveness exist.

A lack of cost effectiveness is frequently cited.^17-19 Jiranek estimate use of ALBC in 50% of patients would cost $117 million in healthcare spending. ²⁰ Yayac et al estimate that at a cost of nearly $300 per case, ALBC would be cost-effective if it leads to a 1% reduction in PJI rate. ¹⁹ In their study of 2511 primary TKAs, nonselective use of ALBC did not reduce PJI rates, nor was it cost-effective. ¹⁹

Development of antibiotic resistance is another major concern.^6,21 Resistance is theorized to occur by drug elution at subtherapeutic levels, which may allow for bacterial colonization of cement and the emergence of resistance.^6,22 Holleyman et al found a higher incidence of gentamycin resistance in Staphylococcus in the setting of gentamycin loaded bone cement in primary arthroplasty. ²¹ In contrast, routine use of tobramycin impregnated cement at one high-volume institution over a 6-year period did not change the profile of organisms most commonly responsible for PJI, nor the resistance profiles of the two most common organisms—S. aureus and coagulase negative Staphylococcus. ²³

Evidence in Select Populations

Given these potential drawbacks, use of ALBC may be restricted to high-risk cases. It has been proposed that patients with inflammatory arthropathies, immunosuppression, insulin-dependent diabetes, previous joint infections, malnourishment, malignant tumor, or hemophilia may benefit from prophylactic ALBC. ²⁰ However, Qadir et al used the aforementioned criteria (with the addition of obesity) and did not find a decrease in infection rates in 1486 primary TKAs at 1 year. ²⁴ In contrast, Chiu et al performed a small prospective RCT on 78 diabetic patients undergoing primary TKA and found that the group receiving cefuroxime impregnated cement developed less PJI. ²⁵ Chiu et al demonstrated a similar advantage in Taiwanese Veterans. ²⁶ Recent data from the Kaiser Permanente Total Joint Replacement Registry and in the San Francisco Veteran’s Affairs Health Care System seem to also support a benefit in patients with diabetes ¹⁸ and in the veteran population, ²⁷ respectively. Veterans may unfortunately be considered a high-risk cohort due to relatively high rates of substance use disorder and medical comorbidities. ²⁷ Both of these investigations studied commercially available PMMA cement mixed with aminoglycosides.^18,27 Studies with results supporting ALBC for primary TKA in select populations are demonstrated in Table 1. High-level evidence is limited at the current time, and additional trials enrolling patients at highest risk for PJI with standardized protocols on ALBC are warranted to provide guidance in primary joint arthroplasty.

Table 1.

Studies With Results Supporting ALBC for Primary TKA in Select Populations.

Cement	Viscosity	Antibiotic	Dose (per 40 g Bag of Cement)	References	Sample Size	Practice Setting	Population	Study Design
Simplex P (Howmedica)	Medium	Cefuroxime	2 g	Chiu, 2001 25	78	Taipei Veterans General Hospital a	Diabetic b	Prospective single blinded, randomized
Palacos R + G (Heraeus)	High	Gentamycin	0.5 g	Bendich, 2020 27	15,972	U.S. Veterans Health Administration (VHA) Hospitals	Veteran population. Patients that received ALBC had a higher proporiton of ASA >2, CCI>0, higher mean BMI and greater percentage of diabetes mellitus, Hepatitis C and Tobacco use.	Retrospective case control
Cemex with gentamicin (Tecres)	Not specified c	Gentamycin	1 g	Namba, 2020 18	16,644 d	Kaiser Permanente	Diabetic	Cohort study on registry data
CMW1 with gentamicin (DePuy Synthes)	High	Gentamycin	1 g
CMW2 with gentamicin (DePuy Synthes)	High	Gentamycin	1 g
Cobalt HV with gentamicin (DJO surgical)	High	Gentamycin	0.5 g
Cobalt MV with gentamicin (DJO surgical)	Medium	Gentamycin	0.5 g
Palacos R + G (Heraeus)	High	Gentamycin	0.5 g
Simplex P with tobramycin (Stryker)	Medium	Tobramycin	1.0 g

^aStudy done in practice setting without “clean-air measures” such as laminar flow or body exhaust suits. Additional antibiotic regimen included IV cefazolin (500 mg) and gentamicin (80 mg) preoperatively, cefazolin 500 mg six-hourly and gentamicin 80 mg 12-hourly for 36 hours postoperatively, cefazolin (500 mg six-hourly) was given orally for 7 days.

^bExcluded rheumatoid arthritis, psoriasis, previous knee surgery, any type of infection of the lower limb, osteomyelitis, malignant tumor, or who were undergoing immunosuppressive treatment.

^cOffered in low, medium, and high viscosity.

^dTotal sample size of 87,018 patients. Data analyzed on subgroup population with diabetes displayed.

Scientific Background

If ALBC is to be carefully employed, two major considerations include: (1) effective use of antibiotics and (2) maintenance of the cement’s mechanical strength. Classically, in order to be used in ALBC, an antibiotic must be available as a powder, water soluble (in order to elute from PMMA), should not combine with the PMMA nor effect its mechanical properties appreciably, and should be heat-stable (i.e., the antibiotic maintains its structure during the exothermic process of cement curing). ²⁸ With prophylactic ALBC, though, heat sensitivity is less pertinent. ²⁹ When cement cures in vivo (as compared to externally with spacers), it does not reach a temperature threshold that will substantially affect the antibiotics minimum inhibitory concentration.^30,31

Still, targeted therapy is paramount. Elution of antibiotics from cement into local tissues occurs through diffusion in proportion to the concentration gradient, following Fick’s law. ²⁸ Antibiotics must be able to elute from cement at concentrations that are either bactericidal, or at least as high as the minimum inhibitory concentration for a given organism. The majority of antibiotic elution occurs in the first 48–72 h after implantation, and concentrations may be subtherapeutic after day 5 ³⁴ despite months of continued elution.

Commonly used commercially prepared ALBC include broad-spectrum aminoglycosides gentamycin and tobramycin. Palacos (Zimmer Biomet, Warsaw, IN) and Simplex-P cement (Styker, Mahwah NJ) are offered with 0.5–1 g of gentamicin and 1 g of tobramycin per 40 g bag of PMMA, respectively. While this may be effective in most cases, several exceptions are important to consider.

The most common organisms implicated in PJI (S. Aureus and coagulase negative Staphylococcus ³² ) may be resistant to aminoglycosides. Up to 12% and 21% of Staphylococcus aureus and 43% and 65% of coagulase negative Staphylococci have demonstrated resistance to gentamicin and tobramycin, respectively. ³³

Additionally, Enterococcus, another commonly implicated gram-positive organism, ³² is inherently resistant to aminoglycosides. ³⁴ In order to add gram-positive coverage for these species, vancomycin and daptomycin may be used. Adding vancomycin may carry additional advantage; combining tobramycin and vancomycin is synergistic, resulting in increased vancomycin elution.^34,35

Further Considerations

When choosing a cement, careful consideration should be given to the elution profile. Two broad types of PMMA cement exist: high viscosity (HVC) and low viscosity (LVC). High viscosity cement is appealing for its decreased mixing and waiting time, with longer working and hardening time. HVC also demonstrates greater antibiotic elution, ³⁶ though it has associated with aseptic TKA loosening. ³⁷ In an analysis of the American Joint Replacement Registry, Palacos with Gentamicin, Cobalt Gentamicin (DJO Surgical, Austin, TX) and Smartset Gentamycin (DePuy Synthes, Warsaw, IN) were the most commonly used commercial high viscosity ALBCs. ³⁸ Simplex P with tobramycin and Palacos LV + G were the most commonly used low viscosity ALBCs. ³⁸ The surgeon must weigh the benefit of ease of use and increased drug elution against the potential increased risk for aseptic loosening.

As an alternative to commercially prepared mixtures, ALBC may be mixed by the surgical team during the procedure. While using premanufactured ALBC may save operative time, mixing performed by the surgical team decreases cost. ³⁹ In 2014, Gutowski et al highlighted an additional per-case cost of $7.88 and $138.66 when vancomycin and tobramycin were hand-mixed vs $420 when premanufactured PMMA with tobramycin was used, respectively. ³⁹ When hand mixed, antibiotics can be mixed into cement in a vacuum with commercially available mixers. Consideration should be given to mixing in a vacuum at negative atmospheric pressure, which decreases porosity and can improve fatigue life. ⁴⁰ Decreased porosity does, however, decrease antibiotic elution. ⁴¹ Again, the surgeon must consider the benefit of drug elution against the theoretical impact on longevity.

Dosing of antibiotics is important, as increasing amounts of antibiotic powder demonstrate a dose dependent decrease in shear ⁴² and compressive strength below acceptable standards. ⁴³ If hand-mixing, 1.0 g of antibiotics is commonly utilized per 40 g bag of cement ²⁰ in parallel to the maximum dose of antibiotic in commercially available ALBC. Higher doses may be cautiously considered. In 2018, the ICMMI stated that most cement maintains mechanical strength with up to 2.0 g of antibiotics per 40 g of cement as a fixation interface during reimplantation after PJI.^{5, 24} Increased dosages (approximately 4 g total per 40 g of cement) are employed in temporary antibiotic spacers. ⁵ Commonly used antibiotics include tobramycin (1–4.8 g), gentamycin (0.25–4.8 g), and vancomycin (0.5–4 g), though various powdered, water-soluble, heat-stable antibiotics may be used based on the sensitivity of the organism being treated.^5,29 Evidence is emerging that antibiotics previously thought to be heat labile, such as cefazolin, may in fact still be effective when cured in cement. ⁴⁴ Carli et al have provided a list of antibiotics that can be employed effectively, even when cured ex-vivo and higher temperatures are reached. ²⁹

Conclusion

Prophylactic use of antibiotic loaded cement may be considered in select patients. Indiscriminate use is not recommended, as it may be ineffective, increase cost, and the potential effects on antibiotic resistance remain unknown.